THE COMMISSION OF THE EUROPEAN COMMUNITIES,
Having regard to the Treaty establishing the European Community, and in particular Article 152(4)(a) thereof,
Having regard to 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(1), and in particular points (b), (d), (e), (f), and (i) of Article 28 thereof,
Whereas:
(1) Directive 2004/23/EC lays down standards of quality and safety for the donation, procurement and testing of all human tissues and cells intended for human applications, and of manufactured products derived from human tissues and cells intended for human applications, so as to ensure a high level of human health protection.
(2) In order to prevent the transmission of diseases by human tissues and cells for human applications and to ensure an equivalent level of quality and safety, Directive 2004/23/EC calls for the establishment of specific technical requirements for each one of the steps in the human tissue and cell application process.
(3) The use of tissues and cells for application in the human body carries a risk of disease transmission and other potential adverse effects in recipients. That risk can be reduced by careful donor selection, testing of each donation and the application of procedures to procure tissues and cells in accordance with rules and processes established and updated according to the best available scientific advice. Therefore, all tissues and cells, including those used as starting material for the manufacture of medicinal products, to be used in the Community should meet the quality and safety requirements laid down in this Directive.
(4) Reproductive cells have, due to the specific nature of their application, specific quality and safety characteristics that are taken into account in this Directive.
(5) For the donation of reproductive cells between partners that have an intimate physical relationship, it is justified to require less stringent biological testing, given that in this case the risk for the recipient is considered less than for donation from third parties. In order to minimise the risk of cross-contamination, biological testing of the donor will be necessary only when the donated cells will be processed, cultured or stored.
(6) This Directive is based on international experience drawn upon through an extensive consultation, the Council of Europe’s Guide to safety and quality assurance for organs, tissues and cells, the European Convention on Human Rights, the Council of Europe’s Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine (Oviedo, 4.IV.1997), with its additional protocols, and recommendations from the World Health Organisation. In particular, with regard to further additional biological testing for donors originating from high-incidence areas of specific diseases or whose sexual partners or parents originate from high-incidence areas, Member States will refer to existing international scientific evidence. The Directive is consistent with the fundamental principles set out in the European Charter of Fundamental Rights.
(7) The measures provided for in this Directive are in accordance with the opinion of the Committee set up by Directive 2004/23/EC,
HAS ADOPTED THIS DIRECTIVE:
For the purposes of this Directive, the following definitions apply:
‘reproductive cells’ means all tissues and cells intended to be used for the purpose of assisted reproduction;
‘partner donation’ means the donation of reproductive cells between a man and a woman who declare that they have an intimate physical relationship;
‘direct use’ means any procedure where cells are donated and used without any banking;
‘quality system’ means the organisational structure, defined responsibilities, procedures, processes, and resources for implementing quality management and includes all activities which contribute to quality, directly or indirectly;
‘standard operating procedures’ (SOPs) means written instructions describing the steps in a specific process, including the materials and methods to be used and the expected end product;
‘validation’ (or ‘qualification’ in the case of equipment or environments) means establishing documented evidence that provides a high degree of assurance that a specific process, SOP, piece of equipment or environment will consistently produce a product meeting its predetermined specifications and quality attributes; a process is validated to evaluate the performance of a system with regard to its effectiveness based on intended use;
‘traceability’ means the ability to locate and identify the tissue/cell during any step from procurement, through processing, testing and storage, to distribution to the recipient or disposal, which also implies the ability to identify the donor and the tissue establishment or the manufacturing facility receiving, processing or storing the tissue/cells, and the ability to identify the recipient(s) at the medical facility/facilities applying the tissue/cells to the recipient(s); traceability also covers the ability to locate and identify all relevant data relating to products and materials coming into contact with those tissues/cells;
‘procurement organisation’ means a health care establishment or a unit of a hospital or another body that undertakes the procurement of human tissues and cells and that may not be accredited, designated, authorised or licensed as a tissue establishment.
1.With the exception of partner donation of reproductive cells for direct use, Member States shall ensure that the procurement of human tissues and cells is accredited, designated, authorised or licensed only when the requirements in paragraphs 2 to 12 are met.
2.Procurement of human tissues and cells shall be carried out by persons who have successfully completed a training programme specified by a clinical team specialising in the tissues and cells to be procured or a tissue establishment authorised for procurement.
3.The tissue establishment or procurement organisation shall have written agreements with the staff or clinical teams responsible for donor selection, unless they are employed by the same organisation or establishment, specifying the procedures to be followed to assure compliance with the selection criteria for donors set out in Annex I.
4.The tissue establishment or procurement organisation shall have written agreements with the staff or clinical teams responsible for tissue/cell procurement, unless they are employed by the same establishment or organisation, specifying the type(s) of tissues and/or cells and/or test samples to be procured and the protocols to be followed.
5.There shall be standard operating procedures (SOPs) for the verification of:
(a)donor identity;
(b)the details of donor or donor family consent or authorisation;
(c)the assessment of the selection criteria for donors as detailed in Article 3;
(d)the assessment of the laboratory tests required for donors as detailed in Article 4.
There shall also be SOPs describing the procedures for procurement, packaging, labelling and transportation of the tissues and cells to the point of arrival at the tissue establishment or, in the case of direct distribution of tissues and cells, to the clinical team responsible for their application or, in the case of tissue/cell samples, to the laboratory for testing, in accordance with Article 5 of this Directive.
6.Procurement shall take place in appropriate facilities, following procedures that minimise bacterial or other contamination of procured tissues and cells, in accordance with Article 5.
7.Procurement materials and equipment shall be managed in accordance with the standards and specifications laid down in Annex IV, section 1.3, and with due regard to relevant national and international regulation, standards and guidelines covering the sterilisation of medicines and medical devices. Qualified, sterile instruments and procurement devices shall be used for tissue and cell procurement.
8.Procurement of tissues and cells from living donors shall take place in an environment that ensures their health, safety and privacy.
9.Where appropriate, the staff and equipment necessary for body reconstruction of deceased donors shall be provided. Such reconstruction shall be completed effectively.
10.The procedures for the procurement of tissues and cells shall be carried out in accordance with the requirements specified in Article 5.
11.A unique identifying code shall be allocated to the donor and the donated tissues and cells, during procurement or at the tissue establishment, to ensure proper identification of the donor and the traceability of all donated material. The coded data shall be entered in a register maintained for the purpose.
12.Donor documentation shall be maintained in accordance with section 1.4 of Annex IV.
The competent authority or authorities shall ensure that donors comply with the selection criteria set out in:
Annex I for donors of tissues and cells, except donors of reproductive cells;
Annex III for donors of reproductive cells.
1.The competent authority or authorities shall ensure that:
(a)donors of tissues and cells, except donors of reproductive cells, undergo the biological tests set out in point 1 of Annex II;
(b)the tests referred to in point (a) are carried out in compliance with the general requirements set out in point 2 of Annex II.
2.The competent authority or authorities shall ensure that:
(a)donors of reproductive cells undergo the biological tests set out in points 1, 2 and 3 of Annex III;
(b)the tests referred to in point (a) above are carried out in compliance with the general requirements set out in point 4 of Annex III.
The competent authority or authorities shall ensure that the tissue and/or cell donation and procurement procedures and the reception of tissues and/or cells at the tissue establishment comply with the requirements set out in Annex IV.
The competent authority or authorities may authorise the direct distribution of specific tissues and cells from where the procurement is carried out to a health care establishment for immediate transplantation.
1.Member States shall bring into force the laws, regulations and administrative provisions necessary to comply with this Directive by 1 November 2006, at the latest. They shall forthwith communicate to the Commission the text of those provisions and a correlation table between those provisions and this Directive.
When Member States adopt those provisions, they shall contain a reference to this Directive or be accompanied by such a reference on the occasion of their official publication. Member States shall determine how such reference is to be made.
2.Member States shall communicate to the Commission the text of the main provisions of national law which they adopt in the field covered by this Directive.
This Directive shall enter into force on the 20th day following its publication in the Official Journal of the European Union.
This Directive is addressed to the Member States.
Selection criteria for donors are based on an analysis of the risks related to the application of the specific cells/tissues. Indicators of these risks must be identified by physical examination, review of the medical and behavioural history, biological testing, post-mortem examination (for deceased donors) and any other appropriate investigation. Unless justified on the basis of a documented risk assessment approved by the responsible person as defined in Article 17 of Directive 2004/23/EC, donors must be excluded from donation if any of the following criteria applies:
people diagnosed with Creutzfeldt–Jakob disease, or variant Creutzfeldt-Jacob disease, or having a family history of non-iatrogenic Creutzfeldt-Jakob disease;
people with a history of rapid progressive dementia or degenerative neurological disease, including those of unknown origin;
recipients of hormones derived from the human pituitary gland (such as growth hormones) and recipients of grafts of cornea, sclera and dura mater, and persons that have undergone undocumented neurosurgery (where dura mater may have been used).
For variant Creutzfeldt-Jakob disease, further precautionary measures may be recommended.
the occurrence of haemodilution, according to the specifications in Annex II, section 2, where a pre-transfusion sample is not available; or
treatment with immunosuppressive agents.
Children aged less than 18 months born from mothers with HIV, hepatitis B, hepatitis C or HTLV infection, or at risk of such infection, and who have been breastfed by their mothers during the previous 12 months, cannot be considered as donors regardless of the results of the analytical tests.
Children of mothers with HIV, hepatitis B, hepatitis C or HTLV infection, or at risk of such infection, and who have not been breastfed by their mothers during the previous 12 months and for whom analytical tests, physical examinations, and reviews of medical records do not provide evidence of HIV, hepatitis B, hepatitis C or HTLV infection, can be accepted as donors.
pregnancy (except for donors of umbilical cord blood cells and amniotic membrane and sibling donors of haematopoietic progenitors);
breastfeeding;
in the case of haematopoietic progenitor cells, the potential for transmission of inherited conditions.
| HIV 1 and 2 | Anti-HIV-1,2 |
| Hepatitis B | HBsAg Anti HBc |
| Hepatitis C | Anti-HCV-Ab |
| Syphilis | See 1.4 (below) |
Textual Amendments
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if blood, blood components and/or colloids were infused in the 48 hours preceding blood sampling or if crystalloids were infused in the hour preceding blood sampling;
:
if blood, blood components and/or colloids were infused in the 48 hours preceding death or if crystalloids were infused in the hour preceding death.
Tissue establishments may accept tissues and cells from donors with plasma dilution of more than 50 % only if the testing procedures used are validated for such plasma or if a pre-transfusion sample is available.
In the case of living donors (except allogeneic bone marrow stem-cell and peripheral blood stem-cell donors, for practical reasons), blood samples must be obtained at the time of donation or, if not possible, within seven days post donation (this is the ‘donation sample’).
Where tissues and cells of allogeneic living donors can be stored for long periods, repeat sampling and testing is required after an interval of 180 days. In these circumstances of repeat testing, the donation sample can be taken up to 30 days prior to and 7 days post donation.
Where tissues and cells of allogeneic living donors cannot be stored for long periods and repeat sampling is therefore not possible, point 2(5)(a) above applies.
Donor selection criteria and laboratory testing do not need to be applied in the case of partner donation of reproductive cells for direct use.
Reproductive cells that are processed and/or stored and reproductive cells that will result in the cryopreservation of embryos must meet the following criteria:
the clinician responsible for the donor must determine and document, based on the patient’s medical history and therapeutic indications, the justification for the donation and its safety for the recipient and any child(ren) that might result;
the following biological tests must be carried out to assess the risk of cross-contamination:
| HIV 1 and 2 | Anti-HIV-1,2 |
| Hepatitis B | HBsAg Anti-HBc |
| Hepatitis C | Anti-HCV-Ab |
In case of sperm processed for intrauterine insemination and not to be stored, if the tissue establishment can demonstrate that the risk of cross contamination and staff exposure has been addressed through the use of validated processes, biological testing may not be required;
where HIV 1 and 2, hepatitis B or hepatitis C test results are positive or unavailable, or where the donor is known to be a source of infection risk, a system of separate storage must be devised;
[F1HTLV-I antibody testing must be performed for donors living in, or originating from, high-prevalence areas or with sexual partners originating from those areas or where the donor’s parents originate from those areas;]
in certain circumstances, additional testing may be required depending on the donor’s travel and exposure history and the characteristics of the tissue or cells donated (e.g. Rh D, malaria, CMV, T. cruzi);
positive results will not necessarily prevent partner donation in accordance with national rules.
The use of reproductive cells other than for partner donation must meet the following criteria:
donors must be selected on the basis of their age, health and medical history, provided on a questionnaire and through a personal interview performed by a qualified and trained healthcare professional. This assessment must include relevant factors that may assist in identifying and screening out persons whose donation could present a health risk to others, such as the possibility of transmitting diseases (such as sexually transmitted infections), or health risks to themselves (e.g. superovulation, sedation or the risks associated with the egg collection procedure or the psychological consequences of being a donor);
the donors must be negative for HIV 1 and 2, HCV, HBV and syphilis on a serum or plasma sample, tested in accordance with Annex II, point 1.1, and sperm donors must additionally be negative for chlamydia on a urine sample tested by the nucleic acid amplification technique (NAT);
[F1HTLV-I antibody testing must be performed for donors living in, or originating from, high-prevalence areas or with sexual partners originating from those areas or where the donor’s parents originate from those areas;]
in certain circumstances, additional testing may be required depending on the donor’s history and the characteristics of the tissue or cells donated (e.g. RhD, malaria, CMV, T. cruzi).
for autologous donors, Annex I, point 2.1.1 applies;
genetic screening for autosomal recessive genes known to be prevalent, according to international scientific evidence, in the donor’s ethnic background and an assessment of the risk of transmission of inherited conditions known to be present in the family must be carried out, after consent is obtained. Complete information must be provided, in accordance with the requirements in force in Member States. Complete information on the associated risk and on the measures undertaken for its mitigation must be communicated and clearly explained to the recipient.
For donation by partners (not for direct use), blood samples must be obtained within three months before the first donation. For further partner donations by the same donor, further blood samples must be obtained according to national legislation, but no later than 24 months from the previous sampling.]
that consent for the procurement has been obtained in accordance with Article 13 of Directive 2004/23/EC; and
how and by whom the donor has been reliably identified.
understood the information provided;
had an opportunity to ask questions and been provided with satisfactory responses;
confirmed that all the information provided is true to the best of his/her knowledge.
the medical records of the donor;
an interview with a person who knew the donor well, for deceased donors;
an interview with the treating physician;
an interview with the general practitioner;
the autopsy report.
the donor identification (first name, family name and date of birth — if a mother and child are involved in the donation, both the name and date of birth of the mother and the name, if known, and date of birth of the child);
age, sex, medical and behavioural history (the information collected must be sufficient to allow application of the exclusion criteria, where required);
outcome of body examination, where applicable;
haemodilution formula, where applicable;
the consent/authorisation form, where applicable;
clinical data, laboratory test results, and the results of other tests carried out;
if an autopsy was performed, the results must be included in the record (for tissues and cells that cannot be stored for extended periods, a preliminary verbal report of the autopsy must be recorded);
for haematopoietic progenitor cell donors, the donor’s suitability for the chosen recipient must be documented. For unrelated donations, when the organisation responsible for procurement has limited access to recipient data, the transplanting organisation must be provided with donor data relevant for confirming suitability.
the identification, name and address of the tissue establishment to receive the cells/tissues;
donor identification data (including how and by whom the donor was identified);
description and identification of procured tissues and cells (including samples for testing);
identification of the person who is responsible for the procurement session, including signing;
date, time (where relevant, start and end) and location of procurement and procedure (SOP) used, including any incidents that occurred; where relevant, environmental conditions at the procurement facility (description of the physical area where procurement took place);
for deceased donors, conditions under which the cadaver is kept: refrigerated (or not), time of start and end of refrigeration;
ID/batch numbers of reagents and transport solutions used.
The report must also contain the date and time of death where possible.
Where sperm is procured at home, the procurement report must state this and must contain only:
the name and address of the tissue establishment to receive the cells/tissues;
the donor identification.
The date and time of procurement may be included, where possible.
At the time of procurement, every package containing tissues and cells must be labelled. The primary tissue/cell container must indicate the donation identification or code and the type of tissues and cells. Where the size of the package permits, the following information must also be provided:
date (and time where possible) of donation;
hazard warnings;
nature of any additives (if used);
in the case of autologous donations, the label must state ‘for autologous use only’;
in the case of directed donations, the label must identify the intended recipient.
If any of the information under points (a) to (e) above cannot be included on the primary package label, it must be provided on a separate sheet accompanying the primary package.
When tissues/cells are shipped by an intermediary, every shipping container must be labelled at least with:
TISSUES AND CELLS and HANDLE WITH CARE;
the identification of the establishment from which the package is being transported (address and phone number) and a contact person in the event of problems;
the identification of the tissue establishment of destination (address and phone number) and the person to be contacted to take delivery of the container;
the date and time of the start of transportation;
specifications concerning conditions of transport relevant to the quality and safety of the tissues and cells;
in the case of all cellular products, the following indication: DO NOT IRRADIATE;
when a product is known to be positive for a relevant infectious disease marker, the following indication: BIOLOGICAL HAZARD;
in the case of autologous donors, the following indication: ‘FOR AUTOLOGOUS USE ONLY’;
specifications concerning storage conditions (such as DO NOT FREEZE).
consent/authorisation; including the purpose(s) for which the tissues and cells may be used (i.e. therapeutic or research, or both therapeutic use and research) and any specific instructions for disposal if the tissue or cells are not used for the purpose for which consent was obtained;
all required records relating to the procurement and the taking of the donor history, as described in the donor documentation section;
results of physical examination, of laboratory tests and of other tests (such as the autopsy report, if used in accordance with point 1.2.2.);
for allogeneic donors, a properly documented review of the complete donor evaluation against the selection criteria by an authorised and trained person;
in the case of cell cultures intended for autologous use, documentation of the possibility of medicinal allergies (such as to antibiotics) of the recipient.
consent; including the purpose(s) for which the tissues and cells may be used (such as reproductive only and/or for research) and any specific instructions for disposal if the tissue or cells are not used for the purpose for which consent was obtained;
donor identification and characteristics: type of donor, age, sex, presence of risk factors and, in the case of a deceased donor, the cause of death;
partner identification;
place of procurement;
tissues and cells obtained and relevant characteristics.