Human body elements, including tissues, cells, blood and blood components can be used for therapeutic purposes in human recipients and extracorporal applications, such as bone marrow transplant or cord blood transplant for the treatment of blood cancer, blood transfusion, skin transplant for burns treatment, or corneal grafting for restoration of sight. It also includes gametes donated for in vitro fertilization. Depending on the types of human body elements, they can be donated both or either by living or dead donors in accordance with national legislations.
In that context, minimum quality and safety standards have to be respected in accordance with European Union (EU) law.
The relevant EU legislation is mainly constituted by Directive 2002/98/EC of the European Parliament and of the Council of 27 January 2003 setting standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components and by 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. These main directives have been completed by various other texts, mainly European Commission’s Directives on more specific and technical aspects, such as certain technical requirements for the donation, procurement and testing of human tissues and cells (Commission Directive 2006/17/EC), traceability requirements, notification of serious adverse reactions and events and certain technical requirements for the coding, processing, preservation, storage and distribution of human tissues and cells (Commission Directive 2006/86/EC), or certain technical requirements for blood and blood components (Commission Directive 2004/33/EC). The EU legislation covers all steps of the transplant process from donation, over collection/procurement, testing, processing, preservation, storage to distribution. It is also applicable to the first steps of developments (donation, collection/procurement and testing) of medicinal products based on blood or blood components or tissues and cells (Blood based medicinal products or Advanced Therapy Medicinal Products) or of medical devices based on tissues and cells (mainly non-viable tissues and cells of human or animal origin). For the full list of relevant EU legislation, please see at the bottom of this page.
More specifically, it shall be highlighted that the European Commission holds tow rapid alert platforms: on for blood “RAB” and for Tissues and cells “RATC”. Both of them include four common types of alerts: Quality and safety defects; Information Notices; Epidemiological Notices; and Bilateral inquiries. RATC also includes a fifth type of alerts on Illegal and fraudulent activities. These platforms allow Member States’ competent authorities to create and launch alerts to each other and to request information with regard to serious and adverse reactions and events in order to rapidly assess risks linked to blood, tissues and cells distributed across border and to take appropriate measures (Article 8 of Directive 2006/86/EC, and Article 9 of Directive 2005/61/EC). Annual summaries of activity provide an overview of the functioning of both RAB and RATC. These platforms are used in parallel with national vigilance systems.
National competent authorities are in charge of implementing and overseeing the implementation of the EU legislation both for tissues and cells, and for blood and blood components: mainly for designating, authorising, accrediting or licensing blood establishments and tissues and cells establishments, and for organising inspections and appropriate control measures. They can also provide stricter requirements that those established by the EU legislation as it exists for tissues and cells testing requirements as well as for blood donor testing requirements.
Moreover, the European Union is also funding research projects and joint actions with national authorities in order to strengthen the quality and safety of substances of human origin or to improve their availability as well as to support their donation or supply. The list of EU funded actions on substances of human origin is available on the European Commission’s website here.
Finally, it should be highlighted that a European Commission’s proposal for a new Regulation on substances of human origin merging the current standards of quality and safety for blood and tissues and cells has been published on 14 July 2022. It constitutes the beginning of the legislative process to reform the current applicable EU legislation.
Stakeholders
Donor “means every human source, whether living or deceased, of human cells or tissues” (Directive 2004/23/EC, Article 3.c)
Tissue establishment “means a tissue bank or a unit of a hospital or another body where activities of processing, preservation, storage or distribution of human tissues and cells are undertaken. It may also be responsible for procurement or testing of tissues and cells » (Directive 2004/23/EC, Article 3.o)
Blood establishment “shall mean any structure or body that is responsible for any aspect of the collection and testing of human blood or blood components, whatever their intended purpose, and their processing, storage, and distribution when intended for transfusion. This does not include hospital blood banks.” (Directive 2002/98/EC, Article 3. e)
Hospital blood bank “shall mean a hospital unit which stores and distributes and may perform compatibility tests on blood and blood components exclusively for use within hospital facilities, including hospital based transfusion activities.” (Directive 2002/98/EC, Article 3. f)
Responsible person is a qualified person with relevant diploma and experience who is responsible for ensuring that activities linked to every unit of blood or blood components are conducted in compliance with national law, providing required information to the national competent authority, implement the requirements of the EU Directives on blood or on tissues and cells. (article 17 of Directive 2004/23/EC, article 9 of Directive 2002/98/EC)
Challenges
One of the main challenges here is to know whether the human body elements used for therapeutic applications in human are transplants or whether they have been transformed into medicinal products based on blood or blood components or into Advanced Therapy Medicinal Products.
If they are transplants, they will be regulated by the European Directives on tissues and cells or on blood and blood components for their entire development pathway from the donation, procurement, testing, processing, preservation, storage and distribution and by national laws transposing these Directives and sometimes providing specific and more stringent national rules than the European ones.
If they are medicinal products based on blood or blood components or Advanced Therapy Medicinal Products, the human body elements used for therapeutic applications in human will have to comply successively with two different set of legislations along their development pathway: first, the European Directives on tissues and cells or on blood and blood components for their donation, collection/procurement and testing, second the European pharmaceutical legislation for their following steps of development into medicinal products.
Moreover, some Member States apply the blood directives (blood establishment authorization) while other apply the tissues and cells directives (tissues and cells establishment authorization) for blood cells when used as a starting material for the manufacture of ATMPs. Nevertheless, both donors and patients remain similarly protected as long as the two sets of legislations (tissues and cells, and blood and blood components) provide for equivalent standards of quality and safety. On this topic, see for instance in the UK, the agreement between the Human Tissue Authority (in charge of the implementation of the tissues and cells rules) and the National Medicines Agency (MHRA in charge of the implementation of the blood rules) allowing the collection of blood as a starting material for an ATMP to be performed under either a Tissues and Cells or Blood Establishment Licence.
Finally, an evaluation of the Blood and the Tissues and Cells EU legislations conducted in 2017 has identified several shortcomings although it has confirmed “the very good levels of overall safety and quality in these sectors (less than one serious patient reaction for every 12,000 applications)”. These shortcomings of the current Blood and Tissues and cells EU legislations are: the current rules are no longer up to date with the dynamic blood, tissues and cells sectors; key oversight principles are not sufficiently robust; some citizen groups, such as donors and offspring are not adequately protected; the legislation does not keep pace with innovation; requirements are insufficient to support sufficiency and a sustainable supply for all blood, tissues and cells.
Of note, the proposal moves the legislation from two main and distinct directives (on human blood and blood components, and on human tissues and cells) to one regulation on substances of human origin. This will allow to reduce the current diverging implementations of the directives as long as the regulation will be directly applicable without requirement of national transpositions. The global approach proposed on substances of human origin will also allow to cover substances of human origin currently unregulated or regulated in divergent ways: breast milk, faecal or intestinal microbiota transplants, bedside preparations of substances of human origin.
Chapter I “General provisions” defines the subject matter and the scope of application of the Regulation; introduces the description of SoHO activities and describes the possibility for Member States to set more stringent measures; describes certain exclusions (such as solid organs) and partial applicability when SoHOs are used to manufacture products regulated by other Union legislation, or as the starting and raw material thereof (such as medicinal products based on blood and advanced therapy medicinal products)
Chapter II “Competent Authorities” covers the designation of competent authorities which are responsible for the SoHO supervisory activities (and the possibility to delegate certain of these activities), the general principles for their functioning (independence and impartiality, transparency), their responsibilities and obligations, and their communication together (within the SoHO sector) and with authorities of other regulated sectors (mainly medical devices and medicinal products including advanced therapy medicinal products in particular).
Chapter III “SoHO Supervisory Activities” covers all activities competent authorities undertake vis-à-vis SoHO entities or processes, including several obligations such as to maintain a register of SoHO entities, to have a system and a procedure for the authorisations of SoHO preparations and SoHO establishments, to conduct inspections (with possible joint inspections) of SoHO establishments, as well as obligations related to data publication, traceability, vigilance and, SoHO Rapid Alerts.
Chapter IV “General Obligations on SoHO Entities” notably covers regarding registration, authorization, export, import, activity data collection and reporting, traceability and coding, application of the Single European Code to SoHOs distributed for human application (except for some specific SoHOs), and vigilance notifications.
Chapter V “General Obligations on SoHO Establishments” (a sub-set of SoHO entities that process and store SoHOs) covers the obligations to have a system and a procedure for their authorisations, a Quality Management system, and to designate a physician responsible for specific tasks.
Chapter VI “SoHO Donor Protection” includes provisions and standards and how to implement them to ensure donor protection.
Chapter VII “Recipient and Offspring Protection” includes provisions and standards and how to implement them to ensure the protection of patients treated with SoHO (recipients) and offspring from medically assisted reproduction.
Chapter VIII “Supply Continuity” notably covers the obligation for Member States to have national SoHO emergency plans and the responsibilities of competent authorities and entities regarding supply alerts for critical SoHOs (obligation to have an emergency plan in place), as well as the conditions for derogation from certain obligations and to provide national additional measures in case of emergencies.
Chapter IX “SoHO Coordination Board” establishes a new coordination board (with composition and functioning) to support Member States in the implementation of this new legislation.
Chapter X “Union Activities” covers the activities organized at the European Union level: training and exchange of competent authorities’ personnel, Commission controls in Member States, support provided by the Commission for the implementation of the Regulation, and cooperation with the European Directorate for the Quality of Medicines & Healthcare at the Council of Europe.
Chapter XI “EU SoHO Platform” describes the general functionalities of this platform supporting information sharing between authorities and with SoHO entities
Chapter XII “Procedural Provisions” regarding confidentiality and data protection obligations, the exercise of delegation, the urgency procedure, the committee procedure, establishment by Member States of penalties applicable to infringements.
Chapter XIII “Transitional Provisions” regarding the current Blood and Tissues and Cells EU legislations, and the adoption of certain delegated and implementing acts.
Chapter XIV “Final Provisions” relates to the repeal of the current Blood and Tissues and Cells EU legislations, evaluation, dates of entry into force and application of the new Regulation.
The full legislative process of revision of this EU legislation can be followed here and the full history of the revision process is detailed on a dedicated European Commission webpage here.
European Union Legislation
Human blood and blood components
Commission Directive (EU) 2016/1214 of 25 July 2016 amending Directive 2005/62/EC as regards quality system standards and specifications for blood establishments (Text with EEA relevance) C/2016/4641, OJ L 199, 26.7.2016, p. 14–15
Commission Directive 2014/110/EU of 17 December 2014 amending Directive 2004/33/EC as regards temporary deferral criteria for donors of allogeneic blood donations (Text with EEA relevance), OJ L 366, 20.12.2014, p. 81–82
Commission Implementing Directive 2011/38/EU of 11 April 2011 amending Annex V to Directive 2004/33/EC with regards to maximum pH values for platelets concentrates at the end of the shelf-life Text with EEA relevance, OJ L 97, 12.4.2011, p. 28–29.
Directive 2005/62/EC of 30 September 2005 implementing Directive 2002/98/EC of the European Parliament and of the Council as regards Community standards and specifications relating to a quality system for blood establishments (Text with EEA relevance), OJ L 256, 1.10.2005, p. 41–48, CELEX number: 32005L0062
Commission Directive 2005/61/EC of 30 September 2005 implementing Directive 2002/98/EC of the European Parliament and of the Council as regards traceability requirements and notification of serious adverse reactions and events (Text with EEA relevance), OJ L 256, 1.10.2005, p. 32–40, CELEX number: 32005L0061
Commission Directive 2004/33/EC of 22 March 2004 implementing Directive 2002/98/ECof the European Parliament and of the Council as regards certain technical requirements for blood and blood components (Text with EEA relevance), OJ L 91, 30.3.2004, p. 25–39, CELEX number: 32004L0033
Directive 2002/98/EC of the European Parliament and of the Council of 27 January 2003 setting standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components and amending Directive 2001/83/EC; OJ L 33, 8.2.2003, p. 30–40, CELEX number: 32002L0098
Commission Directive (EU) 2015/566 of 8 April 2015 implementing Directive 2004/23/EC as regards the procedures for verifying the equivalent standards of quality and safety of imported tissues and cells (Text with EEA relevance), OJ L 93, 9.4.2015, p. 56–68, CELEX number: 32015L0566
Commission Directive (EU) 2015/565 of 8 April 2015 amending Directive 2006/86/EC as regards certain technical requirements for the coding of human tissues and cells (Text with EEA relevance), OJ L 93, 9.4.2015, p. 43–55, CELEX number: 32015L0565
Commission Directive 2012/39/EU of 26 November 2012 amending Directive 2006/17/EC as regards certain technical requirements for the testing of human tissues and cells Text with EEA relevance, OJ L 327, 27.11.2012, p. 24–25, CELEX number: 32012L0039
2010/453/EU: Commission Decision of 3 August 2010 establishing guidelines concerning the conditions of inspections and control measures, and on the training and qualification of officials, in the field of human tissues and cells provided for in Directive 2004/23/EC of the European Parliament and of the Council (notified under document C(2010) 5278) Text with EEA relevance, OJ L 213, 13.8.2010, p. 48–50, CELEX number: 32010D0453
Commission Directive 2006/86/EC of 24 October 2006 implementing Directive 2004/23/EC of the European Parliament and of the Council as regards traceability requirements, notification of serious adverse reactions and events and certain technical requirements for the coding, processing, preservation, storage and distribution of human tissues and cells (Text with EEA relevance), OJ L 294, 25.10.2006, p. 32–50, CELEX number: 32006L0086
Commission Directive 2006/17/EC of 8 February 2006 implementing Directive 2004/23/EC of the European Parliament and of the Council as regards certain technical requirements for the donation, procurement and testing of human tissues and cells (Text with EEA relevance), OJ L 38, 9.2.2006, p. 40–52, CELEX number: 32006L0017
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, OJ L 102, 7.4.2004, p. 48–58, CELEX number: 32004L0023
Proposal for a Regulation of the European Parliament and of the Councilon standards of quality and safety for substances of human origin intended for human application and repealing Directives 2002/98/EC and 2004/23/EC)