What Reliance, Annex 1, And AI Mean For The Future Of GMP
A conversation between the EMA's Brendan Cuddy and Life Science Connect's Jon O'Connell
As pharmaceutical manufacturing grows more global, digital, and operationally complex, regulators are under pressure to modernize how they oversee quality and compliance. That means moving beyond traditional inspection and review models toward approaches that can better address international supply chains, evolving manufacturing science, and emerging technologies such as AI.
Brendan Cuddy, a lead scientific officer at the EMA and chair of agency's Good Manufacturing and Distribution Practice Inspectors Working Group, is closely involved in efforts to expand regulatory reliance, support Annex 1 implementation, strengthen inspector training, and develop the agency’s thinking on AI in GMP environments. He spoke at the 2026 ISPE Europe Annual Conference earlier this year and agreed to answer some of our questions after the event.
He explains how the EMA and its partners are trying to reduce duplication without lowering standards, and where more legal, operational, and technical work is still needed.
We've heard quite a bit about reliance over the last year. Can you share insights from successful initiatives? Which ones need more work?
Cuddy: Over the past year, reliance has continued to move from concept to implementation, with several EMA initiatives demonstrating tangible impact. A notable example is EMA’s reliance pilots for post authorization changes, conducted with WHO and regulators outside the EU. These pilots allow authorities to use EMA’s scientific assessments for major quality-related variations through concurrent reviews, helping reduce duplication and mitigate supply risks. As of early 2025, multiple pilots were underway involving authorities from around 100 countries.
Another well-established example is EMA’s participation in the WHO Collaborative Registration Procedure, where non-EU regulators can rely on EMA assessment and inspection reports to speed up national decisions while preserving full regulatory independence. EMA’s international collaboration frameworks further support this model.
EMA is also actively contributing to the ICMRA Pharmaceutical Quality Knowledge Management System (PQKMS), which aims to strengthen reliance and convergence in quality assessments and inspections globally. Under PQKMS, regulatory authorities, including EMA, are piloting collaborative assessments of post-approval quality changes and hybrid inspections, where one authority leads on-site and others participate remotely. These pilots have shown that regulators can align decisions within days of each other and have now been extended through 2026.
On good manufacturing practice (GMP) inspections, information sharing through EudraGMDP enables partner authorities to access EU GMP compliance data and supports inspection reliance beyond traditional EU boundaries. In parallel, the Inspectors Working Group (IWG) continues to harmonize guidance and procedures, ensuring consistent interpretation of GMP and good distribution practice (GDP) requirements across regions. The IWG supports the European Commission in establishing mutual recognition agreements (MRAs), a deeper form of reliance, so MRA partners recognize and rely on each other’s inspection outcomes. The IWG has also worked on unilateral reliance measures so EU inspectorates can rely on inspections performed by PIC/S authorities in certain circumstances.
Are we moving closer to a model that meaningfully reduces redundancy?
Cuddy: We are slowly moving toward a regulatory model that reduces redundancy of scientific and technical requirements. However, extending reliance more consistently and across the full product life cycle will require further legal alignment, operational experience, and continued trust building among authorities. While change may be slow, there is still a willingness at global level to find solutions to implement reliance, and as a result there are ongoing initiatives.
You mentioned new training initiatives. What new technologies or processes are you focusing on?
Cuddy: The GMDP IWG has developed an inspectors training strategy that recognizes training and capacity building as a strategic objective for the group, and this is line with the EU network strategy 2025 – 2028. The IWG has formed a drafting group on inspector training to provide a more detailed implementation plan for the training strategy. The drafting group is developing an EU GMP inspector training and competency curriculum and seeks to make use of the existing opportunities for inspector training, such as through PIC/S and also to support EU-specific inspector training events through coordination and collaboration. A scheme of observed inspections called the joint inspector training programme is also available to allow a trainee from one member state to observe an inspection in another member state.
The group works through EU programs to secure funding for trainees to attend training courses. Courses range from basic inspector training skills such as writing inspection reports to quality risk management to data integrity and innovative technologies and processes.
We know Annex 1 implementation remains a stubborn challenge, and companies, especially smaller biotechs, have struggled during inspections. Where do you see the most friction happening? Any advice for those companies in our audience?
Cuddy: Annex 1 implementation has undoubtedly been a demanding regulatory shift in recent years, and at the IWG we have discussions with industry associations through our annual interested parties meeting about what we can do as regulators to assist with implementation. Currently the IWG is working with PIC/S on an interpretation document for inspectors that will assist inspectors in the interpretation of key areas that manufacturers have highlighted to us.
From our perspective, concepts such as contamination control strategy, aseptic process simulations, and barrier technologies may be well understood by manufacturers, but they require coherent end-to-end application. Inspections may reveal gaps where controls exist, and so rationale, integration, or life cycle management may not be clearly demonstrated to the inspector.
For smaller organizations, the challenge is often one of proportionality. Annex 1 does not demand perfection overnight, but it does expect a clear understanding of risk, solid scientific reasoning, and evidence of continual improvement. This is where difficulties can arise if companies treat requirements as isolated checklist items rather than elements of a holistic system.
I cannot offer advice, but it seems to me that manufacturers have to be able to explain during an inspection the control strategy in clear terms, show how monitoring and simulations inform decisions, and demonstrate that risks are actively managed rather than retrospectively justified. A well-articulated science-based and risk informed strategy will go a long way toward building confidence during inspection.
The draft Annex 22 guidance introduces a framework for AI/ML in GMP settings. EMA has received many comments calling for risk-based approaches to frontier technologies like probabilistic models and digital twins, rather than a categorical ban. How should we think about safety and risk when evaluating more complex models?
Cuddy: The feedback clearly emphasizes the importance of a risk-based, use-case-driven approach to AI/ML in GMP, rather than a purely technology-based classification. From a regulatory perspective, the key task for the Annex 22 drafting group will be to evaluate the current draft text and decide if an adjustment can be made to the text to move from whether a model is deterministic or probabilistic to consideration of the impact it has on product quality, patient safety, and how risks can be mitigated using QRM principles.
The Annex 22 drafting group is currently considering the best approach to take for such an approach in the final Annex 22 Guideline, so EMA has requested further input from stakeholder associations in an expert workshop that will take place on June 30, 2026, to address this point.
The Annex 22 drafting group has requested feedback on six main topics to help strengthen their evaluation of a risk-based approach.
- Topic 1: Regulatory pathways for adaptive/probabilistic AI models in GMP
- Topic 2: Technical reliability and incident response
- Topic 3: Human oversight and accountability
- Topic 4: Validation and life cycle management
- Topic 5: Strategic risk and compliance limits
- Topic 6: Cybersecurity and outsourced activities
Participation in the expert meeting will be by invitation only, but it will be broadcast on the EMA website at this link.
Sticking with Annex 22 for another moment, most of the comments ask for a dedicated section on training data and bias. What do those comments tell us about the industry's need for greater clarity on EMA's expectations for training data quality and limiting bias?
Cuddy: The comments on training data and bias highlight a clear and consistent message from stakeholders that there is a need for greater clarity and predictability in regulatory expectations for AI enabled systems.
From a GMP perspective, the interest in a dedicated section reflects the recognition that data quality is foundational to system performance. Industry is looking for guidance on how to demonstrate that training data are representative, relevant, and appropriately controlled, and how risks — such as bias, drift, or gaps in data — should be identified and managed.
Importantly, many of these concepts are not entirely new. They can be mapped to familiar GMP principles such as data integrity, validation, and knowledge management. However, AI introduces additional complexity, particularly where models learn from data and evolve over time.
The Annex 22 drafting group is currently considering the best approach to take in the final Annex 22 Guideline.
How do recent activities in the IWG play globally? Are you working toward alignment with partner authorities? Can you discuss any areas that require extra attention?
Cuddy: Activities of the GMP/GDP Inspectors Working Group (GMDP IWG) are increasingly global in both reach and impact. The GMDP IWG is a core expert group in the agency and within the wider European medicines regulatory network and this is where the EU inspectorate network aligns approaches internally and with our international partners who observe meetings, including WHO, PIC/S, EDQM, and authorities linked through MRAs, EU candidate countries, and the United Kingdom. This global engagement supports consistent oversight of complex international supply chains and helps harmonization of inspection standards and interpretation.
The 2026–2028 GMDP IWG work plan, aligned with the European Medicines Agencies Network Strategy (EMANS 2028), places strong emphasis on international collaboration, inspection reliance, and risk-based oversight as core enablers of effective regulation. We want to support convergence of inspection outcomes and more efficient use of global inspectorate capacity, while maintaining high public health standards. Our modernization of the GMP guidelines is proceeding in close collaboration with PIC/S so that changes to the EU GMP Guidelines are harmonized at a global level through the PIC/S GMP Guidelines.
A key example of an emerging area is the pharmaceutical quality system (PQS) effectiveness pilot, which the GMDP IWG is running to explore how the robustness of a manufacturer’s PQS, particularly for risk-based change management, can be demonstrated through inspections and reflected in regulatory oversight.
The recent revision of the variation regulation aimed to streamline the variation framework and improve efficiency for industry and regulators, and there has been a lot of simplification and rationalization to support this aim. A new element introduced into the framework is the product life cycle management document, the PLCM. A new article in the regulation, article 6a, introduces additional regulatory tools. This provides a legal basis for tools, some of which were already in the framework — such as design space and the PACMP — and they had defined change categories in the guideline, which allows us to introduce the PLCM.
The PLCM is defined in ICH Q12 and is seen as a communication tool to support harmonization for global life cycle management. The important thing about these tools is that they usually rely on enhanced pharmaceutical development approaches (QbD) and increased product and process understanding. Their scientific and technical details are defined in ICH guidelines and the procedural and regulatory aspects as they pertain to the EU are defined in the variation regulation and associated guidance.
PLCM is a tool to facilitate global harmonization. It is an important point that within the EU we have a very elaborate and detailed life cycle management system, so the PLCM may not be needed in the EU. We don’t think it is crucial for life cycle management, considering our variation framework, but we recognize that industry sees this tool as an important way to work toward a global life cycle management approach and to have a global dossier. We are happy to facilitate the use of the PLCM within the EU system with that goal in mind.
The pilot assesses whether the European Economic Area (EEA) GMP certificate can serve as primary evidence of pharmaceutical quality system (PQS) effectiveness, supporting the revised EU variations framework applicable from January 2026. Importantly, the pilot is based on PIC/S guidance, helping to align EU practice with international partners, and we hope it will create a foundation for future international reliance approaches and facilitate companies that wish to work toward a global life cycle management approach and to have a global dossier.
More details about the pilot can be found here, on the EMA website.
About The Expert:
Brendan Cuddy is the European Medicines Agency's lead scientific officer and the chairman of the Good Manufacturing and Distribution Practice Inspectors Working Group (GMDP IWG). He received his degree in chemistry from University of Dublin, Trinity College, in Ireland. He holds a master’s degree from the National University of Ireland in quality and operations management and a postgraduate diploma in pharmaceutical manufacturing technology from University of Dublin, Trinity College.