From Tissue Donation To Distribution: Understanding EU Regulatory Requirements In Cell Therapy Clinical Trials
By Jessica Cordes, senior consultant, Clinical Excellence GmbH
Advanced therapy medicinal products (ATMPs), including cell and gene therapies, have the potential to transform treatment paradigms across oncology, immunology, and rare diseases and are expanding into new indications. Yet these clinical trials require an intricate coordination of clinical, logistical, and regulatory components that span international borders, specialized vendors, and evolving regulatory frameworks.
In the EU, among the most critical challenges are those that emerge at the intersection of donor tissue legislation and GMP. For clinical research professionals developing cell therapies and overseeing apheresis procedures, the European Union's Directive 2004/23/EC serves as a foundational framework. Understanding how this directive interacts with GMP — and where its jurisdiction begins and ends — is essential for successful planning, compliance, and execution.
Where GMP And Directive 2004/23/EC Meet
Directive 2004/23/EC, adopted in 2004, sets comprehensive standards for the quality and safety of human tissues and cells intended for human application. It was established to ensure a consistent approach across Member States, enabling safe handling and application of these sensitive biological materials. The directive covers all steps from donation and procurement to testing, processing, preservation, storage, and distribution. While the regulation applies broadly to both autologous and allogeneic use, its practical impact is most keenly felt at the start of the cell therapy manufacturing journey — during donor identification, patient consent, and apheresis.
Importantly, not all aspects of the collection and preparation process fall under GMP. According to the EMA and prevailing regulatory interpretation, the initial donation and collection of cells — for example, through leukapheresis — are not considered part of the manufacturing process and, therefore, are not governed by GMP standards. Instead, they fall under the quality and safety framework outlined in Directive 2004/23/EC. This means that while full GMP does not apply, the procedures must still follow rigorous quality guidelines, often referred to as GMP-like standards. These requirements include meticulous documentation, transparent traceability systems, training verification, and process reproducibility — all of which aim to uphold the safety and integrity of the donor material before it enters the manufacturing environment.
As cell products transition into the manufacturing phase, however, GMP becomes fully applicable. Processing activities such as gene editing, cryopreservation, expansion, and formulation are regulated under GMP and must be carried out in certified facilities with qualified personnel and validated processes. Quality control testing and final product release also fall squarely within the GMP domain. This dual-regulatory environment demands clarity in process handovers, particularly at the interface between tissue establishments and manufacturing facilities. Sponsors must ensure that all transfer protocols, shipping conditions, and documentation requirements are defined and validated so that the chain of identity and custody remains intact.
Challenges And Focus Areas For Minding The Regulatory Gap
This delineation introduces a practical complexity for clinical trial professionals. While the sponsor is ultimately responsible for product quality and patient safety, the first steps in the supply chain — donor screening, apheresis, and initial handling — are typically carried out by independent hospitals or apheresis centers operating under tissue and cell legislation. Bridging this regulatory divide requires cross-functional coordination, detailed planning, and an unwavering focus on documentation and traceability.
In the cell therapy field, success depends not only on scientific innovation but also on operational rigor. For professionals leading clinical trials that involve apheresis and cell-based investigational products, Directive 2004/23/EC provides an essential regulatory foundation. When combined with a clear understanding of GMP boundaries and a proactive operational strategy, it enables trials that are compliant, efficient, and, above all, centered on patient safety and product integrity.
GMP guidelines are pivotal in the production of ATMPs, particularly concerning the starting materials of biological origin. These guidelines ensure that materials are consistently produced and controlled according to quality standards. The document elucidates several critical operational aspects necessary for successful GMP compliance, including the qualification and validation of starting materials. Starting materials, including cells and vectors used to transfer genetic material, must undergo rigorous qualification and validation processes. This includes verifying the source, purity, and potency of materials to ensure they meet predefined specifications. Operationally, this requires close collaboration between procurement teams, quality assurance units, and regulatory bodies to establish robust validation protocols.
Traceability
Traceability of starting materials from donor to final product is fundamental. This involves comprehensive documentation practices that track the journey of biological materials through each stage of production. Implementing an electronic documentation system that integrates clinical, manufacturing, and logistics data is critical for maintaining traceability and ensuring compliance with regulatory frameworks.
Risk Mitigation
Risk mitigation is an operational cornerstone in ATMP manufacturing. Identifying potential risks — such as contamination, variability in biological materials, and logistical challenges — is essential. Developing strategies to address these risks, including implementing backup systems, alternate routes for material transfer, and real-time monitoring technologies, helps ensure uninterrupted production and delivery.
Quality Control And Assurance
Quality control (QC) and quality assurance (QA) are integral to GMP compliance. This includes regularly testing materials for quality attributes, implementing standardized operating procedures (SOPs), and ensuring continuous monitoring and feedback loops. Operational teams must be trained in QC/QA practices, and regular audits should be conducted to verify adherence to quality standards.
Collaboration
Successful ATMP manufacturing requires seamless integration of GMP principles across all operational facets. This involves fostering cross-functional collaboration between clinical teams, manufacturing units, logistics coordinators, and regulatory affairs. Effective communication and coordination are paramount to align efforts and ensure compliance throughout the production life cycle. Cross-functional coordination is achieved through detailed planning and regular communication. Establishing cross-functional teams and holding routine meetings ensures that all stakeholders are aligned. Using project management tools and platforms can facilitate coordination and track progress.
Apheresis centers, in particular, must be carefully assessed and qualified. Sponsors should confirm that these units are accredited under national frameworks aligned with Directive 2004/23/EC. Experience with cell therapy protocols, including cryogenic handling and dry shippers, is critical. Sites must be capable of maintaining an unbroken chain of custody and identity, which often requires additional training on clinical documentation practices, investigational labeling, and reporting of serious adverse events. In many cases, these centers are more accustomed to routine stem cell collection for transplantation than to the rigorous standards required for investigational ATMPs. Therefore, sponsors must provide clinical trial-specific training that reflects the clinical trial’s unique risks, regulatory expectations, and operational constraints.
Equally important is individual staff training. The overlapping responsibilities of tissue legislation, GCP, and GMP require a tailored training program for everyone involved — from apheresis nurses and logistics coordinators to clinical investigators and manufacturing technicians. These programs should address protocol adherence and safety standards as well as build fluency in documentation, cross-functional communication, and escalation procedures. Training effectiveness should be assessed through knowledge tests, practical exercises, and routine refreshers, especially in high-risk areas such as patient identification, sample labeling, and handling of cryopreserved material. Sponsors should maintain training logs and certification records that can be readily produced during audits. For global trials, cultural and linguistic adaptations may be necessary to ensure comprehension across diverse site teams.
Monitoring
Implementing real-time monitoring systems allows immediate detection of anomalies and prompt corrective actions. Feedback mechanisms should be established to continuously improve processes and address emerging challenges. Maintaining an inspection-ready posture across all operational domains is essential. This includes establishing centralized document repositories, maintaining version-controlled SOPs, and conducting internal audits that simulate inspection scenarios. Proactively identifying inspection trends and maintaining communication with regulatory liaisons further enhance readiness.
Documentation
From a compliance standpoint, documentation remains a cornerstone of operational excellence. Directive 2004/23/EC requires that all donation-related records be maintained for a minimum of 30 years. Each donation must be linked to a unique identifier to ensure full traceability from donor to recipient and back. In many EU Member States, this involves the implementation of the Single European Code (SEC). Moreover, vigilance systems must be in place to detect and report any serious adverse reactions or events, both during collection and after administration. These systems must include SOPs for recording, escalating, and investigating any adverse occurrences related to tissue procurement or product use. Integrating these procedures into the sponsor’s broader pharmacovigilance system ensures consistent and complete safety oversight. An essential consideration is to align adverse event reporting timelines and formats across the different regulatory systems — tissue legislation, GCP, and GMP — which may have varying expectations and points of contact.
Informed Consent
Informed consent procedures deserve special attention. Under both Directive 2004/23/EC and the latest 2024 version of the Declaration of Helsinki, participants must receive comprehensive, understandable information about the clinical trial, including the handling of their donated cells, any genetic manipulation, and long-term safety monitoring. Particular care is required for vulnerable populations, who may need additional support to understand their role and rights. Consent forms must be translated into the patient’s native language and include specific language about future use of donated material, the possibility of manufacturing failure, and the limited availability of post-trial access to treatment. Investigators should be trained to discuss these topics empathetically and transparently, reinforcing trust and engagement. Moreover, consent should not be treated as a one-time event; ongoing discussions with the patient help maintain alignment and understanding throughout the trial’s life cycle.
Logistics
Logistics also demands precise synchronization. Cell therapies operate on a just-in-time model, in which patient eligibility, apheresis scheduling, and manufacturing availability must be aligned within tight windows. Cryopreserved products must be shipped in validated containers, tracked in real time, and handled according to good distribution practice principles — even when they are technically still considered investigational. Shipping errors, temperature excursions, or customs delays can have significant consequences, including the loss of patient-derived starting material. Therefore, logistics planning must account for risk mitigation strategies such as backup couriers, alternate flight routes, and temperature monitoring technologies that provide real-time alerts. Moreover, sponsors must assess the reliability of courier partners and ensure that they are trained in chain-of-identity procedures specific to cell therapy.
Final Thoughts On ATMP Regulatory Awareness
As a consultant with a focus on ATMP development, I have seen firsthand how effective cross-functional collaboration and regulatory awareness can transform the feasibility and success of complex trials. By integrating tissue legislation, GMP planning, and GCP oversight into a unified operational framework, we can deliver cell therapy trials that meet both scientific and ethical expectations. For sponsors and professionals navigating this landscape, investing in operational readiness today will pave the way for scalable, sustainable success in the therapies of tomorrow. It is this intersection of precision planning and compassionate execution that will ultimately define the next generation of transformative medicines.
References:
DIRECTIVE 2004/23/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 31 March 2004 on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells
https://eur-lex.europa.eu/eli/dir/2004/23/oj/eng
Questions and answers on the principles of GMP for the manufacturing of starting materials of biological origin used to transfer genetic material for the manufacturing of ATMPs (EMA/246400/2021 )
About The Expert:
Jessica Cordes started her clinical operations career in 2009, working at various companies including Big Pharma and several small to midsize biotech companies. She gained extensive experience on different levels from country study management to global study management and, since 2018, leadership in clinical operations. During her time at Medigene and Immatics, she structured the clinical operations department, built cohesive global teams, and implemented GCP and ATMP-compliant processes. For more than 12 years, she has been working in oncology clinical trials (including hemato-oncology as well as solid tumors) and with ATMPs since 2018. Since 2023, she has been working as an independent consultant and trainer, supporting small companies in building their clinical operations group and setting up their clinical trials for success. She provides a GCP refresher course via her Clinical Excellence Training Academy.