I

Human tissue and cell transplantation has seen a considerable increase in recent years. Directive 2004 /23/EC of the European Parliament and of the Council of 31 March 2004 on the establishment of rules for the application of the rules of the European Parliament and of the Council of the European Parliament and of the Council of the European Union quality and safety for the donation, procurement, evaluation, processing, preservation, storage and distribution of human tissues and cells; Commission Directive 2006 /17/EC of 8 February 2006 on the applies Directive 2004 /23/EC of the European Parliament and of the Council as regards certain requirements technical support for the donation, procurement and evaluation of human tissues and cells; and Commission Directive 2006 /86/EC of 24 October 2006 implementing Directive 2004 /23/EC of the European Parliament and of the Council on concerns traceability requirements, notification of serious adverse reactions and reactions and certain technical requirements for the coding, processing, preservation, storage and distribution of cells and tissues human.

Royal Decree 1301/2006 of 10 November establishing quality and safety standards for the donation, procurement, evaluation, processing, preservation, storage and distribution of cells and human tissues and the rules of coordination and operation for their use in humans are approved, came to transpose the Community legislation into the internal legal order of Spain. However, the Supreme Court has annulled, due to insufficient rank, the aforementioned royal decree by its recent judgment of May 30, 2014.

The decision of the High Court leaves without legal regulation, in matters of donation and transplantation of human cells and tissues, aspects relating to the quality and safety of the donation as important as the voluntariness, the Anonymity between donor and recipient, the altruism and solidarity that characterize the transplant model of the National Health System; the systems of control of the processes that occur from the obtaining of the cells and tissues until their implementation; the conditions to be met by the centres and units for obtaining and implementing them; tissue establishments; systems and channels of information on cell and tissue donation; objectives and access criteria, based on the objective assessment of medical needs, to cells and tissues; public sector and non-profit organisations in the provision of human tissue and cell use services.

the absence of regulation in such areas would lead to the abolition of the existing requirements for the donation of tissues and cells-often not only from EU Member States but also from EU Member States. third countries-and therefore the elimination of measures, with the consequent risk to public health, aimed at preventing the transmission of diseases from the donor to the recipient in tissue implants, some of which are of considerable importance quantitative and qualitative use such as bone marrow, umbilical cord blood, bone tissue or corneas.

In particular, this lack of regulation would lead, firstly, to a lack of guarantees of quality and safety in tissue donations and transplants because of a lack of conditions and requirements to intervene in such scope. The lack of essential requirements, in terms of donor determinations or tissue processing, would generate, for example, a high risk of disease transmission or failure of a transplant.

Secondly, there would also be an absence of necessary public controls as regards the scope of the donation of cells and tissues and, in particular, in the donation of bone marrow.

And in this same line of lack of necessary public requirements and controls, the lack of control over tissue imports and exports is particularly worrying. The declared standard void required prior administrative authorisation for the import or export of tissues from or to third countries. In this situation they could be sent, without any control, tissues of Spanish donors to any country of the world, or could enter into Spain tissues of donors from countries without the minimum criteria of quality with the risk of transmission of diseases to the recipients.

II

This royal decree-law responds to the obvious need to regulate with the required urgency the legal framework indispensable for the immediate materialization of the use of human cells and tissues, as well as of the products These are derived from them, when they are destined to be applied to the human being, in the same terms that already enshrined the royal decree now annulled.

In order to maintain both the guarantees of control of the import and export of tissues from and destined to third countries, as well as the establishment and functioning of Spanish and foreign entities in this In the field of the environment and the legal certainty of patients and professionals in relation to this type of transplant, regulatory action is essential immediately. The aim is to ensure the regulation of many aspects and activities related to the therapeutic application of human tissues and cells for the purpose of avoiding the risk that the current situation entails for public health, which it does not accept. dilate in time the regulation of matter.

At the same time, with this rule, compliance with the normative range required by Article 43.2 of the Spanish Constitution, which enshrines the obligation of public authorities as the guiding principle of social and economic policy to organize and protect public health through preventive measures and health benefits, establishing the "duties and rights of all" in this respect.

The Constitutional Court has pointed out, in judgments such as 182/1997, of 28 October, and 245/2004, of 16 December, that the fact that a matter is subject to the principle of the reserve of law does not permit the conclusion that it is is excluded from the scope of regulation of the royal decree-law, which can penetrate such matters whenever the constitutional requirements of the enabling budget are given and does not "affect", in the constitutional sense of the term, the excluded in Article 86 of the Spanish Constitution, which is necessarily related to the In the presence of a guiding principle of the social and economic policy of Chapter III of Title I of the Constitution.

For all of this, the Government considers that the necessary budgets of extraordinary and urgent need established in Article 86 of the Spanish Constitution that enable it to approve these measures by means of the mechanism of a royal decree-law.

III

This royal decree-law consists of thirty-eight articles distributed in six chapters, a transitional provision, a derogation provision, four final provisions and eight annexes.

Chapter I contains the general provisions relating to the subject matter and scope of the rule; to the definitions; to the principles of free and non-profit; to promotion and advertising; to education and to the training; and confidentiality. The actual decree-law applies to all human tissues and cells, including the hematopoietic progenitor cells of peripheral blood, umbilical cord or bone marrow; the reproductive cells, except in the regulated in Law 14/2006 of 26 May on techniques of assisted human reproduction; fetal cells and tissues, and adult and embryonic stem cells when their purpose is therapeutic use or clinical application. They are excluded from their scope, blood and blood products, with the exception of haematopoietic progenitor cells and human organs. Research procedures with cells and tissues that do not include an application in the human body are also excluded from this scope. This rule also provides for the possibility of establishments between whose activities include the preservation of cells and/or tissues for eventual autologous use, establishing the conditions that such establishments must comply with.

Chapter II contains provisions on donation and procurement of human tissues and cells, differentiating regulation based on whether they come from living donors or deceased donors; on the authorisation of activities in Cells and tissue centres and units of procurement; on the selection and assessment of the donor; on the procedure for obtaining cells and tissues; on the packaging, labelling and transport of cells and tissues to the establishment of tissues; and on the system of collection and custody of information.

Chapter III regulates the processing, storage and distribution of human tissues and cells and, in particular, the authorisation of activities, general operating conditions and the technical and personal responsibility the management of the quality; the reception, processing, storage, labelling, documentation, packaging, distribution, import and export of the tissues and cells; tissue and third-party establishments; and the system of collection and custody of the information.

Chapter IV regulates the application of cells and tissues and, in this framework, the authorisation of the application of cells and tissues in centres or units of application; access to cells and tissues and general conditions of application; the system of collection and custody of information and clinical research.

Chapter V regulates the information, monitoring and biosurveillance systems and, in this field, the registers of centres and units for the collection and application of human tissues and tissue establishments and donors. Haematopoietic progenitors; the general information system; traceability and coding and biosurveillance systems.

Chapter VI regulates the inspection, evaluation and accreditation of excellence in centers and services, as well as violations and penalties.

The single transitional provision regulates the application of this rule, retroactively, to the legal situations arising and to the proceedings initiated prior to the entry into force of the royal decree, except in (a) what is referred to as non-favourable or restrictive sanctioning provisions for individual rights. The single repeal provision provides for the relevant regulatory repeal. The final provisions regulate the title of competence; the incorporation of European Union law; the faculty of development and modification; and the entry into force of the rule.

Finally, the eight annexes regulate, respectively, the minimum requirements and conditions for the authorizations of tissue establishments and centers or units for obtaining and applying cells and tissues; the requirements clinical trials for the evaluation of tissue and cell donors; laboratory tests required in the assessment of donors, except donor of reproductive cells; selection and evaluation of donor of reproductive cells; procedures for donation, removal of cells and tissues and their reception in the tissue establishment; the minimum information required in the traceability system of origin at the destination of the human tissues and cells obtained for application in humans; the cell and tissue coding system; and the system of biosurveillance.

This royal decree-law, as it determines essential aspects for the protection of the health and safety of persons, both donors and potential recipients, has the condition of basic regulation, under cover Article 149.1.16 of the Constitution, which attributes to the State the competence on the basis and general coordination of health, and in accordance with the provisions of Law 14/1986 of 25 April, General of Health. Article 23, which is issued under the exclusive competence of the State in the field of external health and Article 29, which is issued pursuant to Article 149.1.15, is exempted from the provisions of Article 149.1.15. exclusive competence for the promotion and general coordination of scientific and technical research.

By virtue of all of this, by making use of the authorization contained in Article 86 of the Spanish Constitution, on the proposal of the Minister of Health, Social Services and Equality, after deliberation by the Council of Ministers, in its Meeting of the 4th of July 2014,

DISPONGO:

CHAPTER I

General provisions

Article 1. Object and scope of application.

1. This royal decree-law regulates the activities related to the use of human tissues and cells and the processed products derived from them, when they are destined to be applied in the human being. Regulated activities include your donation, procurement, evaluation, processing, preservation, storage, distribution, application, and clinical research.

2. In the event that the processing, processing, processing, application and clinical investigation of the products derived from the cells and tissues are regulated by specific rules, this royal decree-law will only apply to their donation, procurement and evaluation.

3. Excluded from the scope of this royal decree-law:

a) Cells and tissues used as autologous grafts within the same surgical process.

(b) Blood, components and blood derivatives as defined in Royal Decree 1088/2005 of 16 September laying down the technical requirements and minimum conditions for hemodonation and blood products Transfusion centres and services.

c) The organs or parts of organs, if their purpose is to be used in the human body with the same function as the whole organ.

4. This royal decree-law will apply to reproductive cells in all that is not provided for in Law 14/2006, of May 26, on assisted human reproduction techniques, and in their development regulations.

Article 2. Definitions.

1. For the purposes of this royal decree-law:

a) Storage: maintenance of cells or tissues under controlled and appropriate conditions until distribution.

b) Application: any activity involving the use of cells or tissues in a human receptor and/or in extracorporal applications (the activities of implanting, infusing, grafting, applying or transplanting are included).

(c) Cells: individual cells of human origin or cell groups of human origin when not bound by any form of connective tissue.

d) Reproducing cells: those cells or tissues that can be used for assisted human reproduction.

e) procurement centre or unit: health establishment, hospital unit or any other institution carrying out activities to obtain and extract tissues or cells, or which may enable collection and use of surgical waste for the purposes set out in this standard, and which does not require authorisation as tissue establishment.

f) Human implant or application centre or unit: health establishment, hospital unit or any other institution carrying out human tissue or cell application activities in humans.

g) Quarantine: period in which the tissues or cells extracted are physically isolated or otherwise effective, while waiting for a decision on their acceptance or rejection for use in humans.

h) Critical: fact, action, or event that can potentially have an effect on the quality and safety of the cells and tissues.

i) Distribution: transport and delivery of tissues or cells destined to be applied in the human being.

j) Donation: the fact of donating tissues or human cells destined to be applied in the human being.

k) Donation within the couple: the transfer of reproductive cells from a man to a woman of the same couple who claim to maintain an intimate physical relationship.

l) Donor: any human, living or dead source of human cells and/or tissues.

m) Serious adverse effect: any adverse event linked to the collection, evaluation, processing, storage and distribution of cells and tissues that may lead to the transmission of a disease, to the death of patients, or states that endanger their lives, disabilities or disabilities, or that may result in hospitalization or illness or may prolong it.

n) Establishment of tissues: tissue bank, unit of a hospital or any other centre where processing, preservation, storage or distribution of human tissues and cells is carried out after its The invention relates to a method for producing and using human use. Tissue establishment can also be in charge of tissue and cell procurement and evaluation.

n) Clinical research: research developed through protocols including the procedures for obtaining and applying human tissues and cells in humans, when the efficacy or safety of the procedures or the Cells or tissues are not sufficiently checked or where the therapeutic indication is not sufficiently consolidated, and the purpose of which is to check for any of these points.

o) Obtaining: a process by which human tissues and cells can be available for the purpose of this real decree-law.

p) Organ: a differentiated and vital part of the human body formed by different tissues, which maintains its structure, vascularisation and capacity to develop physiological functions with a level of important autonomy.

q) Preservation: use of chemical agents, alteration of environmental conditions or application of other means during the processing of tissues or cells, in order to prevent or delay biological deterioration or physical of the same.

r) Standardized operational procedures (POEs): documented and authoritative work instructions that describe how to perform activities or perform tests that are usually not described in the work plans or standards of good practice.

s) Processing: operation or operations involving the preparation, handling, preservation and conditioning of tissues and cells intended for human use.

t) Serious adverse reaction: unexpected response from the donor or recipient, including a communicable disease, associated with the procurement or application of tissues and cells in the human being, which is fatal, potentially fatal, disabled, who produces disability or disability, or who leads to hospitalization or illness or who prolongs them.

u) Quality system: comprises the organic structure, the definition of responsibilities, the procedures, processes and resources, which are destined to develop the management of the quality. Includes any activity that contributes to the total quality directly or indirectly.

v) Quality management system: coordinated activities aimed at the management and control of an organisation in relation to quality.

w) Fabric: any constituent part of the human body formed by cells bound by some type of connective tissue.

x) Traceability: ability to locate, locate and identify cells and/or tissues in any step of the process from donation, procurement, processing, evaluation, storage and distribution to reach the The invention also relates to a device for the use of said receptor or to be disestimated and/or destroyed, which carries with it the ability to identify the donor, the tissue establishment and the facility that receives, processes or stores the tissues or cells, as well as the ability to identify the receptors or receptors in which the tissues or cells are applied. Traceability also covers the ability to locate and identify any relevant data for products and materials that are to be in direct contact with cells and/or tissues and which may affect the quality and safety of the products. same.

2. In addition,

following definitions shall apply:

a) Allogeneic use: a process by which cells or tissues are extracted from one person and applied to another.

b) Autologous use: a process by which cells or tissues are extracted and applied to the same person.

c) Possible autologous use: cells and/or tissues are obtained in order to be preserved for future hypothetical application in the same person, without a medical indication established at the time of the obtaining and initiating preservation.

d) Direct use: any procedure in which cells are obtained and used without mediating any type of processing or storage.

e) Validation: documentary evidence that proves, with a high level of guarantee, that a certain process, equipment or part of a team or environmental condition ends up producing, in a consistent and reproducible manner, a certain product that meets the specifications, qualities, and attributes that were predetermined. A process is validated with a view to testing its effectiveness for a given use.

Article 3. Gratuitousness and non-profit.

1. The donation of cells and tissues shall, in any case, be voluntary and altruistic, not being able to receive any economic consideration or remuneration by the donor or by any other natural or legal person.

2. The medical procedures related to the removal shall in no case be burdensome for the living donor, nor for the family in the case of the deceased donor, and the living donor must be guaranteed the necessary assistance for his/her reset.

3. The living donor of cells or tissues may receive compensation from the institution responsible for the extraction, limited, strictly, to cover the costs and disadvantages arising from their obtaining in the form of a diet, refund of income lost or similar economic.

4. The receptor shall not be required to be required by the cells and/or tissues used.

5. The activities of tissue establishments shall not be of a lucrative nature, and the actual costs of the services provided by the development of the authorised activities may be passed on exclusively.

Article 4. Promotion and advertising.

1. The promotion and publicity of the donation or procurement of human tissues and cells will always be carried out in a general way, without seeking a benefit for specific people, and pointing out their voluntary, altruistic and selfless character.

Entities that intend to develop any promotional and advertising activities in support of the donation of human tissues and cells shall request prior authorization from the competent health administrations. For such purposes, the competent health administration shall mean the autonomous community where the activity is intended to be carried out, and the National Transplant Organisation where the intended activities exceed that scope. In any event, the procedure for resolving the authorization or refusal of the development of such activities shall be governed by the provisions of Law No 30/1992 of 26 November 1992 of the Legal Regime of the General Administration and of the Common Administrative Procedure.

2. The promotion and publicity of the centres and services referred to in this royal decree shall be carried out in general and shall be subject to the inspection and control of the competent health authorities, as laid down by the Article 30.1 of Law 14/1986, of 25 April, General of Health.

3. The existence and/or persistence of false, misleading or biased advertising and promotion shall be incompatible with the authorization of activities to obtain, preserve, process, distribute or apply cells and tissues in Spain by the the centre, institution, unit or tissue establishment which has issued such advertising or has contractual relations with the institution which has issued the advertising.

In particular, it will be understood that there is misleading advertising in the case of establishments, centres, units and institutions whose advertising leads to error about the real usefulness of obtaining, processing and preserving human tissues and cells for eventual autologous uses, in accordance with available knowledge and experience.

Article 5. Education and training.

1. The health authorities will promote the information and education of the population in relation to the donation of cells and tissues for human application, both of the benefits they bring to the people who need them and of the conditions, requirements and guarantees that this procedure entails.

2. They will also promote the continuing training of healthcare professionals in this field.

Article 6. Confidentiality.

1. Donors will be guaranteed the confidentiality of all data related to their health and provided to authorized personnel, as well as the results and traceability of their donations, according to Organic Law 15/1999, of 13 of December, for Personal Data Protection.

2. Tissue establishments shall adopt, in the treatment of donor-related data, the high level security measures provided for in the Regulation on the security of automated files containing data from the personal character, approved by Royal Decree 1720/2007 of 21 December, approving the Regulation on the development of Organic Law 15/1999 of 13 December.

3. Personal data shall be of a confidential nature and shall be made available exclusively to the persons concerned, in accordance with the provisions of Law 41/2002 of 14 November 2002, which is a basic regulation of the autonomy of the patient and of rights and the obligations relating to information and clinical documentation and, where appropriate, the judicial authority for the performance of the tasks entrusted to it. Their use shall be limited to care or interest to public health and shall be collected and guarded in accordance with the provisions of Article 10 of Law 14/1986 of 25 April in Organic Law 15/1999 of 13 December, and in the Law 41/2002, dated November 14.

4. The duty of confidentiality shall not prevent the adoption of preventive measures where the existence of risks to individual or collective health is suspected in the terms provided for in Articles 25 and 26 of Law 14/1986 of 25 April, or, in its In accordance with the provisions of the Organic Law 3/1986 of 14 April, Special Measures in the Field of Public Health, Law 41/2002 of 14 November, and the Organic Law 15/1999 of 13 December.

5. Information shall not be provided or disclosed which will allow the identification of donors and recipients of human tissues and cells, nor may the identification data of recipients or vice versa be provided to donors or their family members.

CHAPTER II

Donating and obtaining human tissues and cells

Article 7. Donation and procurement of cells and tissues in living donors.

1. The production of cells and tissues of a living person for further allogeneic application in human beings may be carried out if the donor is older, has full capacity to act and has adequate health and has written his or her informed consent.

The information that will be received by the donor of the physician who is responsible for the extraction, must cover the purpose and nature of the production of the cells and tissues; their consequences and risks; the analytical data to be performed; the recording and protection of the data; and the therapeutic purposes. The protection measures applicable to the donor and the benefits that the use of the extracted tissue or cell group is expected to achieve is also reported.

Consent may be revoked at any time prior to the collection of the cell and/or tissue, except in cases of obtaining hematopoietic progenitors of peripheral blood or bone marrow, in which the may only occur prior to the start of the conditioning treatment at the recipient.

Cells and tissues of minors or persons who are not able to obtain their consent, except in the case of mental illness, mental illness, legal intraining or any other cause, cannot be obtained. for surgical or haematopoietic progenitors or other reproducible tissues or cell groups whose therapeutic indication is or may be vital to the recipient. In these cases, consent will be granted by the person who has the legal representation.

2. The production of cells and tissues of a living person for processing and subsequent autologous use or for their eventual autologous use shall be carried out in accordance with the provisions of paragraphs 1 to 3 of the previous paragraph.

In the case of eventual autologous use, the content of the information provided prior to the procurement must include, in addition to the provisions of the previous paragraph, the indication that the cells and tissues thus obtained be available for allogeneic use in other patients in the event of therapeutic indication; current, truthful and complete information on the state of scientific knowledge regarding therapeutic or research uses; processing and storage conditions in the approved establishments; and any other issue related to the therapeutic utility of obtaining cells and tissues without medical indication established at the time of the procurement and initiation of preservation.

In the case of persons under age or persons who are unable to give their consent, they will be provided by their legal representative.

3. In all the provisions of this Article, the procurement of cells and tissues of a living donor shall be governed by the provisions of Chapter IV of Law 41/2002 of 14 November.

Article 8. Donation and procurement of tissues and cells in deceased donors.

1. The procurement of tissues and cells of deceased persons may be carried out in the event that they have not been expressly aware of their opposition, as provided for in Article 11 of Law 41/2002 of 14 November.

In the case of minors or persons unable to consent, the opposition to the donation may be recorded by those who have been in the life of those who represent them.

2. The production of reproductive material of deceased persons for reproductive purposes shall be governed by the provisions of Law 14/2006 of 26 May on assisted human reproduction techniques.

3. Family members and close associates should be provided with information on the need, nature and circumstances of the procurement, specifying which procedures for the restoration and preservation of the corpse and mortuary healing practices will be carried out

4. The procurement of cells and tissues shall be carried out after the corresponding certification of the death and the practice of law enforcement and judicial proceedings if any.

Article 9. Authorization of activities in the centers and units of cell and tissue procurement.

1. The procurement of tissues and cells may be carried out only in those centres or health units which are duly authorised by the competent health authority, as provided for in Royal Decree 1277/2003 of 10 October 2003. establish the general basis for the authorisation of health centres, services and establishments, and provided that the minimum requirements and conditions set out in Annex I. 1 to this Royal Decree-Law are met.

Without prejudice to specific regulations in respect of each Autonomous Community, the application for authorisation shall contain:

a) The name of the responsible or responsible for the donor and donor assessment process.

b) A detailed memory with the description of the means at its disposal and its adequacy to that specified in the minimum conditions and requirements set out in this standard.

2. These centres and health units shall have a specific authorisation for the production of each type of tissue or cell group, the validity of which shall be extended for a period of not less than two years and not more than four years, to the the term of which may be renewed, after finding that the conditions and requirements which gave rise to its granting remain. In no case shall it be automatically extended.

Any substantial modification to the conditions or requirements which led to the granting of the authorisation must be notified to the competent health authority and may result in its review or even the revocation of the authorisation. authorisation if the amendments entail a substantial alteration of the circumstances justifying the concession.

3. In those cases where it is feasible and necessary to obtain the tissue or cell group outside the hospital or health care or in an unapproved health centre for the production of tissues and/or cells, such procurement must be carried out by professionals integrated in a team to obtain a centre duly authorised for such activity and under the conditions set out in that centre. In these cases the cells and tissue procurement equipment must be in possession of the appropriate authorisation for this specific practice. In any case, the clinical records and samples necessary to ensure that the relevant studies and tests are carried out and specified in the following Article shall be collected.

Article 10. Donor selection and assessment.

1. Tissue procurement shall be carried out in such a way as to ensure that the assessment and selection of the donors is carried out in accordance with the requirements set out in Annexes II, III, IV and V of this Royal Decree-Law, and by staff with the appropriate training and experience. The person responsible for the selection and evaluation procedure shall draw up and sign the relevant report showing compliance with those requirements.

2. The application of selection and assessment criteria shall be based on the application of an analysis of the assessment of risks in relation to the specific use of each tissue or cell group.

3. The results of the donor selection and evaluation procedures shall be duly documented and shall, where appropriate, be communicated in accordance with the terms of Law 41/2002 of 14 November.

4. In the case of donations of multiple tissues or tissues for the purpose of being transplanted in a non-deferred manner, the unit responsible for the process of obtaining the approved center will be responsible for the custody and archiving of all the data derivatives of the donor selection and assessment process, as well as the existence and maintenance of the seroteca.

5. In the event that the cells or tissues obtained are to be sent to another tissue establishment for processing, the process may be responsible for the completion of the evaluation and selection of the cells or tissues. final feasibility and will also have access to data on the assessment of donors and will ensure the custody of the information on the additional assessment. In the same way, you must keep serum samples in case you have performed additional tests on those processed in the procurement center.

6. In the case of donations for specific uses other than clinical transplants, the person responsible for the procurement procedure shall also be responsible for matters relating to the collection and archiving of data and samples from donors.

Article 11. Procurement procedure.

1. The procurement of cells and tissues shall be carried out by means of standardised and validated standardised operating procedures that are suitable for the tissue or cell group to be extracted, which in the case of living donors their health and safety and respect their privacy and comply with the provisions of Annex V.

2. The procurement procedure shall be appropriate to adequately protect the properties of the cells or tissues that are necessary for their clinical use, while minimizing the risks of microbiological contamination.

3. In the case where the tissues and/or cells are to be sent to a tissue establishment for processing, the procedure for obtaining, packaging, labelling, maintenance and transport to such a centre shall be recorded in a document agreed between the procurement unit and the tissue establishment.

Article 12. Packaging, labelling and transport to tissue establishment.

1. The packaging, maintenance, labelling and transport of tissues and cells to tissue establishment shall be carried out by means of standardised and validated standardised operational procedures and shall comply with the provisions of this Regulation. in Annex V.

2. The packaging and transport of tissues and cells should be carried out in such a way as to minimise the risks of contamination and prevent the deterioration of the biological properties necessary for their possible clinical use.

Article 13. System for the collection and custody of information.

1. The centres and units approved for the production of cells and tissues must have a system of collection and custody of the information in their activities which will enable compliance with the provisions on codification and traceability of the royal decree-law.

2. The centres and units approved for the production of cells and/or tissues shall provide the data relating to their activity required by the competent health authorities of their autonomous community, which shall forward them to the National Transplant Organization as provided for in Chapter V of this royal decree-law.

CHAPTER III

Processing, storage, and distribution of human tissues and cells

Article 14. Authorisation of activities in tissue establishments.

1. Activities related to the processing, storage and distribution of human tissues and cells may be carried out only in those centres or health units duly authorised by the competent health authority, following the general bases for the authorisation of health centres, services and establishments established by Royal Decree 1277/2003 of 10 October 2003, provided that the minimum requirements and conditions set out in Annex I. 2 to this Regulation are met. decree-law.

Without prejudice to the specific regulations in respect of each Autonomous Community, the application for authorization must be accompanied by a memory in which compliance with the requirements of this royal decree is collected.

2. These health centres and units shall have a specific authorisation for the development of each of the processes and activities of the previous paragraph for each type of tissue or cell group, as set out in Annex I. 3. The validity of the authorisations shall be extended for a period of time determined not less than two years and no more than four years, at the end of which the renewal may be carried out, subject to a finding that the conditions and conditions of the authorization remain. gave rise to its concession. In no case shall it be automatically extended.

Any substantial modification to the conditions or requirements which led to the granting of the authorisation must be notified to the competent health authority and may result in its review or even the revocation of the authorisation. authorisation if the amendments entail a substantial alteration of the circumstances justifying the concession.

3. Applications for authorisation of activities shall take the action which the tissue establishment shall take in the event of termination of the activity for which the authorisation is sought, including the coverage of the responsibilities. acquired and the consignment to another establishment of duly authorised tissues of the samples of stored cells and tissues, of the sera and of the information necessary to ensure their traceability.

Article 15. General operating conditions for tissue establishments.

1. The processing activities carried out in tissue establishments shall aim at the preparation, preservation and storage of the cells and tissues for clinical use, both autologous and allogeneic, in procedures therapeutics with established medical indications or in human application procedures in cases of properly tested utility and efficacy, or in duly documented clinical research procedures.

2. Tissue establishments shall process, preserve and store cells and tissues in such a way as to ensure their maximum use. In addition and in accordance with the principle of equitable distribution, they shall ensure access to cells and tissues in cases of insufficient availability and for medical reasons for the suitability of the recipients.

3. As provided for in Article 3.5, the competent authorities of the Autonomous Communities shall lay down the rules for the compensation and charge of the costs which may be applied to distributed tissues and cell groups in order to cover expenditure. derivatives of their activity. These charges may only be applied to the application center or unit after the processing or preservation activity is complete and the tissue or cell group is distributed.

4. Tissue establishments that preserve cells and tissues for eventual autologous uses are also required to subscribe to insurance that covers the costs of processing, preservation and storage for the event of the transfer or dispatch of these cells and tissues to another establishment, centre or health unit for allogeneic uses in therapeutic procedures with medical indications established in suitable recipients. The insurance shall also cover the transfer in cases of cessation of the business of the establishment.

Article 16. Quality Management.

1. Tissue establishments shall develop and maintain an updated quality and quality management system integrated into the guidelines and strategies of the tissue establishment and include at least the following documentation:

a) Manuals of operational procedures of the authorized activities and critical processes.

b) Training and reference manuals.

c) Information transmission forms.

d) Data regarding the origin and destination of cell groups or tissues.

e) Information about the traceability of cells or tissues.

f) System of detection and communication of adverse effects and reactions.

2. The documentation referred to must be available for inspections by the competent health authority.

Article 17. Technical and personnel responsible.

1. Each tissue establishment shall appoint a technical officer who shall meet the following conditions:

(a) Possession of a higher university degree in the field of medical or biomedical sciences, issued after complete university studies recognized and approved in Spain as equivalent to university degree higher.

b) Have a proven practical experience of not less than three years in the field of action concerned.

2. The functions and responsibilities of the technical officer include the following:

(a) To ensure that in the area of tissue establishment which is responsible, tissues and cells intended to be applied in humans are processed, stored and distributed in accordance with this real decree-law and the rules applicable to it.

(b) Provide information to the competent authorities on the conditions, requirements and operating arrangements required of tissue establishments by this royal decree-law.

c) Apply in the tissue establishment all conditions and requirements and implement the regulated operating system in this royal decree-law.

3. Tissue establishments shall notify the competent authority of the name and qualifications of the technical officer. Where it is permanently or temporarily replaced, this replacement shall be immediately communicated to the competent authority. Such communication shall include the name and qualification of the replacement and the exact date of the replacement period or its start when it is indefinite.

4. The staff of the tissue establishment involved in the activities related to the processing, preservation, storage or distribution of cells and tissues shall have the necessary qualifications to perform the tasks they are responsible for. entrusted and receiving the relevant training.

Article 18. Receiving cells and tissues.

1. The tissue establishment must have a documented reception procedure to verify that the tissues and cells extracted in the procurement centers or units meet the requirements of this royal decree-law.

2. Tissue and cell shipments that do not meet these requirements should be rejected by tissue establishment.

3. The reception of tissues and cells should be in accordance with the provisions of Annexes V. 2 and VI.

4. The reception process must ensure that there is no risk of contamination with the tissues and cells already deposited and that they are in the process of processing, preservation or storage.

Article 19. Cell and tissue processing.

1. The tissue establishment shall include in its procedural manuals any processing activity of the cells and tissues and shall ensure that they are carried out under controlled conditions. The equipment used, the working environment and the design, validation and control conditions of the processes shall be verified to comply with the requirements set out in Annex I. 3.

2. Any modification of the processes used in the preparation of the tissues or cells shall comply with those requirements.

Article 20. Storage of cells and tissues.

1. Any action related to the storage of cells and tissues shall be documented in the procedure manuals. The storage conditions shall be in accordance with Annex I. 3 in such a way as to ensure that the viability, quality and safety of the cells and tissues are maintained.

2. As provided for in Article 14.3, in the event of cessation of tissue establishment activity, preserved or stored cells and tissues shall be transferred to another duly authorised tissue establishment.

Tissue establishments should ensure the transfer in case of cessation of activity by agreements previously established with other establishments and known by the transplant coordination units of the Autonomous communities.

3. All information on the storage activities shall be duly collected and kept in order to ensure that the availability of the stored tissues and cells can be known at all times.

Article 21. Labelling, documentation and packaging.

The labelling, documentation and packaging procedures shall comply with the requirements set out in Annex

3.

Article 22. Distribution of cells and tissues.

1. The conditions for the distribution and transport of tissues and cells shall be in accordance with Annex I. 3.

2. Transport from tissue establishment to the implant centre or to another tissue establishment shall be carried out by means of the most appropriate means of land or air transport and through systems capable of maintaining viability and functionality of cells and/or tissues. These systems must be specified in documented procedures according to the type of cell or tissue to be moved.

Article 23. Import and export of cells and tissues.

1. The Ministry of Health, Social Services and Equality will authorize the import and export of the tissues and cells referred to in this royal decree-law, prior to the National Transplant Organization. The import, export and transit of these cells and tissues shall be carried out only through the customs offices specified in Annex I to Royal Decree 65/2006 of 30 January 2006 laying down requirements for imports and export of biological samples.

2. Only the importation of tissues and cells shall be permitted if the following circumstances are present:

a) That there is a proven benefit in the use of the tissues and cells that are intended to be applied.

b) That the purpose of the tissues and/or cells is that of their application in humans.

c) That, in the case of cells and tissues that are usually processed in one of the national tissue establishments, there is no availability at that time of such cells and/or tissues.

3. Only the export of tissues and cells shall be permitted if the following circumstances are present:

(a) That there is sufficient availability of such cells and/or tissues in national tissue establishments.

b) There is a medical reason to justify the export.

4. Applications for the import and export of cells and tissues shall be submitted to the National Transplant Organisation for the establishment of tissues, the centre or the unit involved, with the prior knowledge of the coordination unit transplants from the appropriate autonomous community. The National Transplant Organisation will transfer the applications to the General Foreign Health Subdirectorate of the Ministry of Health, Social Services and Equality along with its report for processing.

5. Applications for the import and export of cells and tissues shall specify the institution of origin and destination, respectively, which must comply with quality and safety standards equivalent to those regulated in this royal decree.

6. In order to ensure compliance with the provisions of the previous paragraph, the tissue establishment shall issue a certificate accompanying the application for import and export. In the case of imports of tissues and cells, the certificate shall contain the following information:

(a) A documented technical report showing that the tissue or the form in which the cells have been processed are essential for the therapeutic procedure to be applied and what, or the tissues and/or cells, or The processing method is not available and cannot be provided by the national establishments.

(b) The documentation relating to the institution of origin where the ethical and health guarantees are observed.

(c) A memory of the establishment of tissue of origin where the evaluations and studies (clinical, biological, microbiological and/or immunological) are included, in line with the established law of this royal decree. the selection and evaluation of the donor.

In the case of tissue and cell exports, the certificate shall contain the following information:

a) A report showing sufficient national availability of the tissues and/or cells to be exported.

(b) The documentation certifying the unavailability of the processing method to be used when this is the reason for the output of the tissues and/or cells.

c) A technical memory where the medical reasons for the output of the tissues and/or cells are shown when this is the reason.

d) The documentation that provides proof that data protection is guaranteed.

7. The importation of cells or tissues may be refused or revoked where they do not originate from altruistic donations made in third countries that meet due guarantees.

Article 24. Relations between tissue establishments and third parties.

1. Tissue establishments shall conclude contracts in writing with third parties provided that they develop an activity that influences or may influence the quality and safety of the tissues and/or cells processed, and in particular where:

a) The tissue establishment confide to a third party responsibility for a phase of cell and/or tissue processing.

b) A third party supplies materials or products or provides services that may affect the quality and safety of the cells and/or tissues.

c) A fabric establishment provides a service to another establishment for which it is not authorized.

d) A tissue establishment stores and distributes tissues and/or cells processed or treated by a third party.

2. Tissue establishment will assess the ability of third parties and select those who ensure compliance with the standards set forth in this royal decree.

3. Contracts shall clearly specify the responsibilities of third parties in relation to the processes to be carried out as well as a detailed description of such processes.

4. There will be documented operational procedures where the way to contract is specified, the relationships between the contracting parties and the protocols that each one must follow in relation to the contracted activity.

5. Tissue establishments shall have a record of contracts concluded with third parties, the information of which shall be available to the competent authority and the transplant coordination unit of the autonomous community. corresponding.

6. In the case of a contract resolution, the contracted entity shall forward to the tissue establishment the data and samples which may affect traceability or the quality and safety of cells and tissues. The terms of this reference of samples and information shall be detailed in the procurement procedure and must be included in the service contract.

7. Tissue establishments shall send copies of contracts entered into with third parties to the transplant coordination unit and to the competent authority for the authorisation of such activities in their autonomous community.

8. Where the contracting of the third party implies access by the third party to personal data, the contract must comply with the provisions of Article 12 of the Organic Law 15/1999 of 13 December.

Article 25. System for the collection and custody of information.

1. Tissue establishments shall have a system for the collection and custody of information relating to their activities which ensures the traceability of all processed cells and tissues. In case the system has electronic format, the existence of backups must be ensured.

2. There shall be a documented procedure for the collection and custody of the information. The establishment shall designate a person as responsible for the system of collection and custody of the information in the activities and shall communicate this designation to the transplant coordination unit and to the competent authority of the community. self-contained.

3. Tissue establishments shall transmit quarterly information of their activities to the transplant coordination unit and to the competent authority of the relevant autonomous community and shall at all times be available to them. for the collection and custody of the information.

CHAPTER IV

Application of cells and tissues

Article 26. Authorization of the application of cells and tissues in centers or units of application.

1. The application of human tissues and cells may be carried out only in those centres or health units duly authorised by the competent health authority following the general approval bases for centres, services and health facilities established by Royal Decree 1277/2003 of 10 October 2003, provided that the minimum requirements and conditions set out in Annex I. 4 to this Royal Decree-Law are met.

2. These health centres and units must have a specific authorisation for each application or implant activity of cells and tissues and for each type of cell and tissue. The competent health authority of each autonomous community shall determine the period of validity of the authorisations, which shall not be less than two years and not more than four years, as well as the requirements for their possible renewal.

Any substantial modification to the conditions or requirements which led to the granting of the authorisation must be notified to the competent health authority and may result in its review or even the revocation of the authorisation. authorisation if the amendments entail a substantial alteration of the circumstances justifying the concession.

3. Without prejudice to the specific rules in respect of each Autonomous Community, the application for authorisation of the application shall be accompanied by a memory with the detailed description of the means available to the Centre for the purpose of carrying out the activity. requested and its adequacy to the provisions of this royal decree-law. In addition, the type of tissue or cell group for which the authorisation is sought and the name and training of the person responsible for the implementation team shall be recorded.

4. The competent health authority of the autonomous communities shall notify the National Transplantation Organisation in real time of the authorisations granted, refused and revoked.

5. For the application of human tissues and cells, the consent of the recipient or his legal representatives shall be required in accordance with Law 41/2002 of 14 November.

Article 27. Access to cells and tissues and general application conditions.

1. The cells and tissues stored in tissue establishments shall be available to the tissue and cell application centres or units for allogeneic uses in therapeutic procedures with established medical indications. appropriate receivers.

In case the tissue establishment that has processed and stored the cells and tissues does not have the necessary infrastructure for a complete typing of the cells and tissues to be established. (a) a sample shall be sent to another duly authorised establishment which is equipped with the appropriate infrastructure and which shall be set up as a reference establishment. The distribution of cells and tissues will take into account what is foreseen in this royal decree-law.

2. The autologous application shall be framed in the case of therapeutic procedures of proven efficacy in established medical indications.

In the event that processing activities are performed for eventual autologous uses for which there is no current established medical indication, the cells and tissues thus processed will be available for allogeneic application. as provided for in the first subparagraph.

3. In the case of a tissue or cell group of limited availability, the data of the patients will be centralized waiting to receive the implant in the transplant coordination unit of the autonomous community and in the organization. National Transplant.

4. The application of the tissue or cell group shall be made by the person responsible for the centre or the unit of application to the tissue establishment. A validated copy of the authorisation shall be attached to the application as a centre or unit of application of that tissue or cell group. Tissue establishment shall not distribute the tissue or cell group if the aforementioned copy is not provided.

5. In the absence of tissue processing establishments in the autonomous community itself, or in the absence of the authorised establishments of the requested tissue, the request shall be addressed to the transplant coordination unit of that community. who will forward it to the National Transplant Organization for national or international search.

Article 28. System for the collection and custody of information.

1. The centres and units authorised for the application in humans of human tissues or cells shall have a system of collection and custody of information on the activities carried out in this area, of restricted and confidential access, where the uses and clinical applications made with the data necessary for the identification of the recipients, the tissues and/or cells implanted as well as their provenance, shall be established in such a way as to allow appropriate monitoring in case necessary, as specified in Chapter V.

2. The centres and units authorised for the application of human tissues or cells shall transmit quarterly information from their activities to the transplant coordination unit and to the competent authority of the relevant autonomous community and in Every moment they will have at their disposal their system of collection and custody of the information.

3. Cell and tissue application centres shall inform the establishment of tissues or, where appropriate, the procurement centre which has supplied them with the cells and tissues, on the final destination of the application in humans of such cells or tissues. tissues, and in the event that the application does not eventually occur, the cause that did not make it possible.

Article 29. Clinical research.

1. Clinical research with cells and/or tissues may only be carried out in the procurement and application centres and units and in tissue establishments duly authorised for the development of the research activity.

2. The clinical research projects shall be approved by the competent authority of the autonomous community concerned. For the granting of the authorization, the report of the experts designated for this purpose by the Transplant and Regenerative Medicine Commission of the Interterritorial Council of the National Health System will be required.

3. Applications for authorisation for clinical research projects with cells and/or tissues shall include at least the following information and documentation:

a) Justification and detailed description of the clinical research project.

b) Information on related clinical or basic research procedures and information on the tissues/cell groups to be used and the processing and/or processing and use of the same.

c) Designation of the coordinating and professional center responsible for the project acting as the principal investigator and description of the research team or teams.

d) Identification of participating centers and units, both in the extraction phase and in the implant phase.

e) Identification of tissue establishments when they are different from the extraction or implant centres.

f) The authorities of those responsible for the centres involved.

g) The report of the ethics committee of the project's coordinating center. In the event of not being an implant center the report of the ethics committees of the implant centers involved will be required.

h) The informed consent document.

i) The insurance procurement policy for patients where appropriate.

j) The Report of the Project and Promoter Body Costs.

k) The project quality assurance system protocol.

4. The competent authority of each Autonomous Community shall notify the National Transplant Organization every six months of those clinical research projects that are authorized and in execution in the field of their community. autonomic.

5. The provisions of this article will not apply to the cases of clinical research in cell therapy, which will be regulated according to the provisions of Royal Decree 223/2004 of 6 February, which regulates clinical trials with medicinal products. In these cases, the Spanish Agency for Medicines and Health Products will request a report from the National Transplant Organization.

CHAPTER V

Information, tracking and biosurveillance systems

Article 30. Registration of centers and units for obtaining and applying human tissues and tissue establishments.

1. The National Transplant Organisation, without prejudice to the registration powers of the autonomic authorities, shall develop and maintain a register of tissue establishments and units or centres for the collection and application of cells and authorised human tissues, where the specific activities for which they are authorised shall be specified for each of them. This register will be accessible to the public.

2. The transplant coordination units of the autonomous communities shall communicate in real time to the National Transplantation Organization the information concerning the tissue establishments and the procurement and application centers or units. of tissues and cells which are authorised in the field of their competence, in order to include it in this register. Such information shall include at least the name and location of the establishment, unit or approved centre, the activities for which they are authorised and the periods of validity of those authorisations.

3. The National Transplant Organisation shall appoint a technical officer for the maintenance and custody of the registry.

Article 31. Registration of donors of haematopoietic progenitors.

1. The National Transplant Organisation, without prejudice to the registration powers of the autonomic authorities, shall be the body responsible for developing and maintaining the register of donors of comprehensive haematopoietic progenitors. aggregated information from the National Health System as a whole.

2. The transplant coordination units of the Autonomous Communities shall communicate in real time to the National Transplant Organisation information on the donors of haematopoietic progenitors included in their respective records.

3. The person holding the Ministry of Health, Social Services and Equality may entrust the management of this information to public or private entities that carry out their activities in the field of promotion and publicity in support of the donation of human tissues and cells.

Article 32. General information system.

1. The competent authorities of the autonomous communities shall determine the required information as provided for in Articles 13, 25 and 28 of this royal decree-law, which shall include at least the minimum contents approved by the Transplant Commission. and Regenerative Medicine of the Interterritorial Council of the National Health System.

2. The transplant coordination units or, where appropriate, the competent authorities of the autonomous communities, shall send to the National Transplant Organization with at least six-monthly intervals the information collected in accordance with the Articles 13, 25 and 28 of this royal decree-law.

The National Transplant Organization will develop and maintain a system of collection, custody and analysis of this information, which will have access to the transplant coordination units of the autonomous communities in the terms to be agreed upon in the Transplant and Regenerative Medicine Commission of the Interterritorial Council of the National Health System.

3. The National Transplant Organisation shall draw up an annual report containing information on the establishment of tissues, units or centres for the collection and application of human tissues and cells, as well as activities developed. This report, which shall in no case contain personal data relating to donors and recipients, shall be accessible to the public and shall be transmitted to all the centres and units involved and shall include data of general interest to which due dissemination.

4. The Ministry of Health, Social Services and Equality, through the National Transplant Organisation, will collaborate with the European Commission and the other Member States of the European Union in the development of an information exchange network. between the national registers of tissue establishments and of centres or units for obtaining and applying authorised human tissues and cells.

5. Access to any of the data contained in the information systems regulated in this royal decree-law will be restricted to those persons authorized by both the technical officers of the tissue establishments and those responsible of the units of tissue extraction or implant, such as the transplant coordination units or the competent authorities of the Autonomous Community and, in the field of their competence, by the National Transplant Organisation.

6. All collection and archive systems must comply with the principles laid down in Organic Law 15/1999 of December 13.

Article 33. Traceability.

1. The National Transplant Organization and the transplant coordination units of the autonomous communities will establish, in the terms agreed in the Transplant and Regenerative Medicine Commission of the Interterritorial Council of the National Health System, a system of tracing of origin to the destination of all the human tissues and cells obtained in order to be applied in humans. That system shall collect the information referred to in Annex VI.

2. In the case of embryonic cells of eventual application in humans, the National Transplant Organization and those responsible for the National Bank of Cellular Lines and the Commission for Monitoring and Control of Donation and Use of Cells and Human tissues shall establish a system to ensure the monitoring provided for in the previous paragraph.

3. The information, where appropriate, shall be coded in accordance with the basic standards set out in Annexes VI and VII which will allow for their uniform monitoring. Tissue establishments and units and centres for the collection and application of cells and tissues shall collect the information in real time.

4. Tissue establishments shall collect information on the fate of the cells and tissues distributed for human use. Such information shall be provided by the tissue and cell centres, organisms or units for each particular case, in order to ensure the traceability of the cells and tissues.

5. Origin-to-destination tracing shall apply not only to cellular and tissue products, but also to products and materials that come into contact with such cells and tissues and may have an effect on their quality and safety.

6. The information shall be stored and stored safely for at least 30 years from its codification.

Article 34. Coding system.

1. The Transplant and Regenerative Medicine Commission of the Interterritorial Council of the National Health System, on the proposal of the National Transplant Organization, will establish a single and mandatory coding system, compatible with the systems from other Member States of the European Union, which will allow the unique and unambiguous identification of tissues and cells obtained, processed and distributed for human use.

2. The design of the coding system shall comply with the minimum requirements set out in Annex VII.

3. A technical system shall be developed which supports the coding system and which shall be accessible to all centres and establishments approved for the procurement, processing and application of cells and tissues, as well as for the units of coordination of transplants from the Autonomous Communities and the National Transplant Organization.

Article 35. Biosurveillance system.

1. Since the entry into force of this royal decree-law, a system of biosurveillance will operate which will allow the reporting, recording and reporting of serious adverse effects and effects that may have influenced or could influence the the quality and safety of the cells and tissues and which can be attributed to the processes of obtaining, evaluating, processing, storing and distributing the cells and tissues, as well as any serious adverse reactions observed during or following the clinical application of the cells and/or tissues, and which may be related to their quality and safety.

2. As long as it is not regulated differently, the transplant coordination network of the autonomous communities and the General Administration of the State will function as a network of biosurveillance.

3. All centres or units which obtain and apply cells or tissues as well as tissue establishments shall communicate the existence of any adverse event or reaction in the form and in the terms set out in Annex VIII, through of the aforementioned transplant coordination network.

4. Tissue establishments that process or preserve tissues that may be affected by any serious adverse reaction or effect shall issue a detailed report of possible causes and consequences, as well as of the measures taken and of which they are to be adopted.

5. The National Transplant Organisation is responsible for the communication of the existence of serious adverse effects which could affect other Member States through the notification system established by the European Commission. It shall also notify the regional transplant coordination units where the tissue establishments concerned are located or that they may be affected by a serious adverse effect occurring in another country, all information relating to: event.

6. Tissue establishments are responsible for ensuring that there is a prompt, accurate and verifiable procedure to allow any product that may be related to a serious adverse effect to be removed from the distribution.

CHAPTER VI

Inspection, evaluation and accreditation and violations and sanctions

Article 36. Inspection and evaluation.

1. The competent authorities of the autonomous communities shall carry out periodic inspections to ensure that tissue establishments approved in the field of their competence meet the requirements of this royal decree and apply the quality control measures required in the.

2. The Interterritorial Council of the National Health System, through its Transplant and Regenerative Medicine Commission, will approve an inspection plan at the initiative of the National Transplant Organization and the coordination units of the (b) Transplants of the autonomous communities, in which the periodic inspections provided for in the previous paragraph are envisaged.

3. The Transplant and Regenerative Medicine Commission will raise the general criteria for the Interterritorial Council of the National Health System to ensure that the conditions for carrying out the inspections, the control measures and the training and qualification of the professionals responsible for them, are carried out with a minimum and homogeneous level of competence and results.

4. The interval between two regular inspections will be two years.

5. The competent authorities of the autonomous communities shall organise the extraordinary inspections and the implementation of the control measures they deem necessary for a serious adverse reaction or effect. They shall also organise extraordinary inspections and implement control measures where necessary, at the justified request of the competent authority of another Member State of the European Union, or of the Commission.

6. The inspection shall not only affect tissue establishments but also all third parties with whom contractual relations exist, and shall involve the examination, assessment and verification of any infrastructure, equipment, information, document, or record related to the regulated in this actual decree-law.

7. Requests for special inspection from another Member State or from the Commission must be channelled through the National Transplant Organisation, which will be responsible for transferring the report to the requesting State or the Commission. with the result of the inspection and the control measures applied.

Article 37. Assessment and accreditation of centres and services excellence.

1. The competent authority of each Autonomous Community shall carry out the programmes for the evaluation and accreditation of the centres and services for the procurement, processing, distribution and implantation of cells and tissues in accordance with the criteria to which they are based. refers to the following section.

2. The Transplant and Regenerative Medicine Commission will raise the general criteria for the evaluation and accreditation of centers and services for the Interterritorial Council of the National Health System.

3. The competent authority of each Autonomous Community shall regularly report to the National Transplant Organisation, often at least annually, on the assessment and accreditation activity of the centres and services and their results.

4. As provided for in Article 70.2.d) of Law 14/1986, of April 25, the National Transplant Organization, following agreement of the Transplant and Regenerative Medicine Commission of the Interterritorial Council of the National Health System, may act as a technical entity for the assessment and accreditation of the approved centres and services under this royal decree-law.

Article 38. Infringements and penalties.

Without prejudice to other rules which may be applicable, the offences committed against the provisions of this Royal Decree-Law and its implementing provisions shall be regarded as an infringement in the field of health, as provided for in Chapter VI of Title I of Law 14/1986 of 25 April, and in the other provisions applicable to it.

In the violations in the field of the use of files containing personal data, the provisions of Title VII of the Organic Law 15/1999 of 13 December.

Single transient arrangement. Rule retroactivity.

This royal decree-law shall apply to legal situations arising and to proceedings initiated prior to its entry into force, except as regards non-favourable sanctioning provisions or restrictive of individual rights.

Single repeal provision. Regulatory repeal.

As many provisions of equal or lower rank are repealed, they are opposed to the provisions of this royal decree-law.

Final disposition first. Competence title.

This royal decree-law has a basic character and is dictated by the provisions of Article 149.1.16 of the Constitution, which attributes to the State the competence on the basis and general coordination of health. Article 23, which is issued under the exclusive competence of the State in the field of external health and Article 29, which is issued pursuant to Article 149.1.15, is exempted from the provisions of Article 149.1.15. exclusive competence for the promotion and general coordination of scientific and technical research.

Final disposition second. Incorporation of European Union law.

By this royal decree-law, Directive 2004 /23/EC of the European Parliament and of the Council of 31 March 2004 on the establishment of quality and safety standards for the the donation, procurement, evaluation, processing, preservation, storage and distribution of human tissues and cells; Commission Directive 2006 /17/EC of 8 February 2006 implementing Directive 2004 /23/EC of the European Parliament and of the Council on the Parliament and the Council as regards certain technical requirements for the the donation, procurement and evaluation of human tissues and cells; and Commission Directive 2006 /86/EC of 24 October 2006 implementing Directive 2004 /23/EC of the European Parliament and of the Council as regards the traceability requirements, notification of serious adverse reactions and effects and certain technical requirements for the coding, processing, preservation, storage and distribution of human tissues and cells.

Final disposition third. Development and modification faculty.

The Government is empowered to make the necessary provisions for the development and implementation of this royal decree. The person holding the Ministry of Health, Social Services and Equality is also entitled to amend the annexes of this royal decree in order to adapt them to the advancement of scientific and technical knowledge or to adapt them to the Community rules.

Final disposition fourth. Entry into force.

This royal decree-law will enter into force on the day of its publication in the "Official State Gazette".

Given in Madrid, July 4, 2014.

FELIPE R.

The President of the Government,

MARIANO RAJOY BREY

ANNEX I

Minimum requirements and conditions for the authorisations of tissue establishments and centres or units for the collection and application of cells and tissues

1. The minimum requirements and conditions for the authorisation of medical centres to obtain human tissues and cells for use in humans are:

a) Dispose of a surgical medical unit specialized in the practice of the extraction of the tissue or cell group to be obtained. The person responsible for the extraction procedure shall be designated in each case.

(b) In the event that the use or destination of the cells or tissues is an immediate or non-deferred transplant, there shall be an established relationship with the transplant coordination team.

(c) When the destination of the extracted cells or tissues is their derivation to a tissue establishment for processing, there shall be a collaboration agreement which shall include a protocol agreed with that establishment, the conditions for obtaining, preparing and transporting the tissues or cells until their arrival at the processing establishment.

(d) When the destination of the cells or tissues is their transformation, there shall be a collaboration agreement with the entity responsible for that transformation known and authorised by the competent authority of the relevant autonomous community.

e) Dispose of the appropriate infrastructure and personnel for the correct assessment of the donor and ensure the conduct of relevant studies to rule out the presence of communicable diseases, as stipulated in Annexes II, III and IV. The person responsible for the donor assessment procedures shall be appointed.

f) Dispose of standardized operating procedure for proper verification of:

1. The identity of the donor.

2. º The requirements of the authorization.

3. The selection and evaluation criteria.

4. The completion of the required laboratory tests for evaluation and selection.

g) Dispose of the facilities and means necessary to ensure the conditions for the extraction, preparation and transport of the cells or tissues, as referred to in paragraph c).

(h) Dispose of the appropriate facilities and facilities to ensure the restoration and preservation of the corpse, as well as mortuary practices, in the event that the removal is carried out by a deceased person.

i) Having established documentation of the relations and conditions of extraction with the processing establishments and/or implant of tissues and cells with which it relates, which must be communicated to the authority competent.

j) Dispose of a system of collection and custody of information related to their activities, of restricted and confidential access where they will consist of the extractions made and the necessary data of the donors, of the cells or tissues, as well as the final or intermediate destination thereof. The data relating to the tests and characteristics of the donors shall be kept, specifying the date of completion and the outcome of the tests, in such a way as to enable the appropriate monitoring of the information, if necessary, as provided for in Articles 13 and 31.

k) Maintain a file of serums from allogeneic or potentially allogeneic donors (samples collected for a hypothetical autologous use without current therapeutic indication) for at least 10 years from the last application clinical or date of expiry of the cells/tissues, in order to carry out biological controls if necessary. In the case of reproductive cells, the sera file shall be maintained for two years from the last transfer.

l) Dispose of a standardized operating procedure for the packaging, labeling, and transportation of cells and/or tissues to the point of destination (tissue establishments and transplant equipment in the case of distribution direct).

2. The technical requirements required to qualify for authorisation as tissue establishment are:

a) As for the organization and address:

1. In addition to the Director of the establishment, a technical officer should be appointed in accordance with Article 17.

2. Dispose of an appropriate organizational structure and operating system in which the relationships of dependency and responsibilities of each job position are clearly defined, and that is adapted to the activities for which are requested for authorization.

3. º There must be standardized operating procedures for all the activities for which authorization is chosen.

4. The tissue establishment should be provided by a medical team or have access to medical support that can review, monitor, analyze, and, if necessary, promote certain changes in medical activities. establishment, such as: donor selection, tissue/cell risk assessment, tissue or cell availability in exceptional cases, review and evaluation of tissue/cell monitoring distributed for application or relationships with the centers or units of application among others.

5. You must have a quality management system applied to all the activities to which the establishment of tissues is chosen by the authorization under the conditions set out in Article 16.

6. There should be procedures for minimizing the risks inherent in the management of biological material, while maintaining an adequate level of quality and safety of the cells and tissues. All technical activities of the processing of cells and tissues of the establishment, the environmental conditions and sanitary sanitary conditions of establishment personnel should be covered at this point.

7. A documented procedure must exist to ensure the identification of all tissues and cells at any stage of the activity for which authorization is requested. This identification procedure should be compatible with the state coding system set out in Chapter VI.

b) In terms of personnel:

1. Place sufficient staff and sufficiently prepared to perform the activities for which you are requesting authorization.

2. Dispose of a detailed description of the profile of the jobs, tasks, responsibilities and relationships with other jobs.

3. Dispose of a continuing training program for tissue establishment personnel to ensure that each worker:

i) You have sufficient competence for the development of the tasks entrusted to you.

ii) You have the right knowledge and experience to understand the technical scientific processes that are related to the tasks assigned to you.

iii) Meet the organizational structure, operating system, and quality system of the establishment.

iv) Meet the hygiene-sanitary standards of the establishment in relation to the activities that are carried out there.

v) You are adequately informed of the ethical and legal aspects and the rules of correct practice in relation to the activities of the establishment.

c) In terms of equipment and material:

1. The entire equipment and the material used must be specifically designed and maintained for the intended purpose, minimizing any risk to the recipients or to the staff working in the establishment.

2. º Critical equipment must be identified as such. They should be inspected on a regular and/or regular basis and appropriate preventive measures should be taken in accordance with the manufacturer's instructions. When the equipment can affect critical processes or parameters that mark storage or preservation conditions (temperature, pressure, particle count, pollution levels, etc.) it must be identified as such. In these cases the monitoring, control and warning systems, alarms and correction measures which are more appropriate and required to detect a malfunction, the danger of an unacceptable deviation or a defect, shall be established and must be ensure that critical parameters are kept in acceptable limits all the time.

3. º All new or repaired equipment must be evaluated at the time of installation and must be validated before being used. Information on all the results of these evaluations should be collected and guarded.

4. The activities of maintenance, cleaning, disinfection, sanitation and review of critical equipment should be included in documented procedures, should be carried out on a regular basis and information on the development of These procedures shall be properly collected and guarded.

5. We must have documented procedures for the operation of each critical equipment where the actions to be taken in the event of malfunction or failure will be detailed.

6. The operational procedures for the activities for which the authorisation is requested should include the specifications of the critical equipment and the reagents. The specifications of the additives (i.e. solutions) and packaging materials shall be included. The reagents and critical materials will have to comply with the specifications of Royal Decree 1591/2009 of 16 October 2009 regulating medical devices and Royal Decree 1662/2000 of 29 September on medical devices for in vitro diagnostics.

d) In terms of infrastructure and premises:

1. Dispose of the local and the necessary infrastructures to perform the activities for which authorization is requested.

2. When these activities include the processing of cells or tissues under open exposure conditions, the air quality and cleaning conditions required to minimise the risks of the exposure must be specified. pollution including cross-contamination. The effectiveness of the measures necessary to meet these conditions for validation and monitoring.

3. ° Except in the cases specified in point 4., provided that the cells or tissues are going to processes in open exposure and without a subsequent microbiological inactivation procedure a quality of air is required. Particulate matter and microbiological colonies equivalent to that specified as grade A in Annex I of the European Corrective Standards Guide Manufacturing at the site of processing. For the ambient air of the rest of the work place, an appropriate quality will be required for the activities to be carried out, but at least equivalent to the grade D of the European Guide to Good Standards Manufacturing in the Particulate matter and microbiological colonies refers.

4. No less stringent environmental conditions than those specified in point 3 may be accepted in the following cases:

i) Where validated microbiological inactivation or sterilization procedures are to be applied.

ii) When it has been demonstrated that exposure to a grade A ambient air has harmful effects on the biological properties that are required of the affected tissue/cell group.

iii) When it is demonstrated that the use or procedure of application of the cells or tissues implies a risk of transmission of bacterial or fungal diseases significantly less than the transplantation of cells or tissues.

iv) When it is not technically possible to perform the processing of cells or tissues in a grade A environment, for example when the operating conditions of the equipment required are not compatible with the Grade A environment

5. When one of the assumptions in paragraph 4 is applied, the conditions of the ambient air to be worked on must be specified and must be demonstrated and documented that in these conditions the standards are met. required for the quality and safety of the tissues, bearing in mind the therapeutic or application object and the route or method of application of the cells and/or tissues and the immune situation of the recipient. The appropriate equipment and clothing must be available for both the protection of staff and hygiene in all departments where necessary and shall be accompanied by the corresponding written hygiene and use standards.

6. When the activities for which the authorisation is requested involve the storage of the cells or tissues, the storage conditions must be specified and defined in each case, including the margins of those parameters that are relevant to maintaining the properties of cells or tissues, such as temperature, humidity, or air quality.

7. The measures of the parameters that are critical should be monitored and monitored and must be registered in order to demonstrate that the specifications of the storage conditions are met.

8. A storage infrastructure must be available that clearly allows to separate and distinguish those tissues and cells that are quarantined from those who have been rejected, or those who have been accepted and are available, in order to prevent cross-contamination and simple mixtures. Depending on the tissue or cell in which it is spoken, it will require physically separate areas or a safe segregation system, but in any case the system must be specified and the basic rule of preserving biological conditions and the of security and quality.

9. There must be procedures and rules for access to the premises of the establishment, for internal circulation, for hygiene and maintenance, for the disposal of waste and dirty or waste material and for the restoration of all services following an emergency situation. These procedures shall be subject to control.

e) Regarding documentation, collection and custody:

1. º All standardized operating procedures for the activities for which the authorization is requested must be properly registered, and the documentation must be properly stored and guarded. There must be a system that guarantees this point. Documents should be reviewed periodically and procedures should always be in accordance with the basic specifications of this royal decree-law. The system will ensure the standardization of the work and that all phases can be traced: coding, evaluation of the cells or tissues and the environment in their case, obtaining, processing, preservation, storage, availability, transport and distribution, and that aspects related to quality control and management are kept in mind.

2. º Equipment, materials or personnel involved in critical activities must be properly identified and such identification must be documented.

3. Any changes in the documents of the operating procedures or the rules of action should be reviewed, dated, documented and put in place without delay by the authorized personnel.

4. A system must exist that ensures periodic review of documents, record of changes introduced, and only updated versions will be in use.

5. º The documentation must be recorded so that it is a correct representation of the results and that it is reliable.

6. º Records must be legible and indelible, may be on paper or transferred to any other system validated as a computer support or microfilm.

f) As for quality systems:

1. Audits Shall Be Carried Out at intervals not less than the biennial for the review of all the activities for which the tissue establishment has been authorised. The purpose of the audits is to verify that the approved protocols are working according to the requirements of this royal decree. Both the findings and the corrective measures should be documented.

2. The finding of deviations from the quality standards that have been established will force the development of an investigation that must be documented and that includes the decisions or suggestions on possible preventive measures. or corrective.

3. The fate of cells and tissues entering the definition of "non-conformity" will be decided in accordance with procedures previously established and supervised by the technical officer and the quality area manager. All cells and tissues affected by non-conformities should be identified and accounted for.

4. The corrective actions should be initiated and completed at the appropriate time and effectively. All preventive and corrective actions shall be documented and evaluated as to their effectiveness.

5. The quality management system should be reviewed and there will be a procedure that allows it to be done and that aims to ensure a continuous and systematic improvement in the functioning of tissue establishment.

3. The requirements for the authorization of activities, processing, storage, and distribution of cells and tissues are:

a) For processing:

1. Critical cell and tissue processing processes must be validated. In no case should cells and tissues be dangerous to the recipient or potentially ineffective. This validation shall be based on studies carried out by the tissue establishment itself or on published data or on the evaluation of the clinical results of the cells and tissues that have been distributed by the establishment in the case of processing or preparation of tissues that are consolidated.

2. It must be demonstrated that validation processes can be carried out in the establishment of tissues effectively and systematically.

3. The procedures should be documented as standardized operating procedures, hereinafter POE, and in accordance with the provisions of paragraph 2.e), and must ensure that the activities are carried out according to These POEs.

4. When a microbiological inactivation procedure is to be applied, it must be documented, specified and validated.

5. º Before any changes are made to the processing activities, the modified process must be validated and documented.

6. º Processing activities should be evaluated periodically, to ensure that the desired results are met.

7. Activities to discard cells and tissues that do not meet the required standards should be performed in such a way as to avoid contamination of other cells and tissues, staff, aparatage, or local. as environmental pollution.

b) As for storage:

1. There must be a system of cell and tissue inventory designed so that it is ensured that they cannot be distributed until they have satisfied all the requirements of this royal decree-law. There should be a POE detailing the circumstances, responsibilities and procedures for the release and subsequent distribution of tissues and cells.

2. All storage procedures shall be developed under controlled conditions in such a way as to ensure the conditions of credibility, quality and safety of the cells and tissues.

3. º Existien means of environmental control of the areas of conditioning and storage in order to avoid any situation that could adversely affect the functionality, the integrity or the biological conditions of the cells and tissues.

4. The Maximum storage time must be specified for each type of fabric or cell and storage condition. The period determined should take into account among other issues the possible deterioration of the cell and tissue properties as well as the use to which they are intended.

5. The cells and tissues stored at all stages of processing in tissue establishment should be clearly identified and it should be possible to distinguish clearly between those cells and tissues that are in quarantine and those that are ready to be distributed or those that must be discarded.

6. º Information records should clearly collect all data relating to evolution and processing so that it can be demonstrated that the specifications of this royal decree-law are met before releasing and distribute the cells and tissues. All the medical data, the results of the evaluation tests, the processing data of all cases where a POE was necessary should be available, must be ensured that this has been carried out rigorously by the people authorized for this, and also that all records of the storage conditions controls are available.

If at any time, a computer system is in charge of releasing or facilitating any results of a lab test or validation, there must be a tracking system that can give the auditor information about the responsible for releasing that information.

7. The technical officer defined in Article 17 shall approve a risk assessment document to determine the fate of all stored tissues and cells. This document shall take into account the assessment of the donor and the criteria for selection and acceptance of the results of the tests carried out, as well as any modification of the processing phases which may improve the safety and quality of the tests. cells and tissues.

c) As to its distribution and withdrawal:

1. The conditions and maximum transport time must be defined, which allow the biological and functional properties of cells and tissues to be maintained.

2. º The container must be safe and ensure that the cells and tissues are maintained in the specified conditions. All containers and packaging containers must be validated for the intended purpose.

3. When the distribution is carried out by a third party there must be an agreed contract document that ensures that the required transport conditions are maintained.

4. The staff must be appointed who, within the tissue establishment, is in charge of the withdrawal, indicating the reasons and the need to remove the products and to initiate and coordinate the activities necessary for this purpose.

5. There must be a documented procedure to set the system for withdrawals, and it must include a clear attachment of responsibilities and actions to be initiated. The corresponding modification should be included in accordance with Annex VII.

6. The actions must be undertaken in predefined times and must include tracing and tracking of all tissues or cells that may be involved, with the aim of locating any donor that may have been involved. contributed to an adverse reaction or undesirable effect and to remove all tissues and cells that have been obtained from that donor, as well as to notify the consignees and recipients of the cells and tissues of that donor be at risk.

7. There must be documented procedures for handling cell and tissue requests. The rules of distribution to patients or implant bodies or centres should be documented and accessible to those involved if required.

8. º There must be a documented system for the handling of tissues or cells returned to tissue establishment, including the criteria for acceptance of the inventory if applicable.

d) As for labeling:

1. The tissue establishment must have a labeling system that ensures that the labels or documents comply with the following information requirements:

i) The labeling of the primary container of cells/tissues should show:

1) The identification number or code of the tissue/cell, the type of cells or tissues and the batch when the latter proceeds.

2) Identification of tissue establishment.

3) The expiration date.

4) In case it is for autologous use, this must be specified: "for autologous use". In addition, the donor/recipient identification code will be displayed.

5) In the case of targeted donations, the receiver will be identified.

6) When it is known that cells/tissues are positive for an infectious disease marker, they should be identified as risk samples: "biological risk".

If, for reasons of space, it is not possible to include the information referred to in points (4) and (5), it must be provided in a document added to the primary container. This document must be packed with the primary container in such a way as to ensure that they remain together.

(ii) The information below may appear on the label or in an attached document:

1) Description, definition, and, if relevant, the dimensions of the tissue or cell product.

2) Morphology and functional data when relevant.

3) Date of cell/tissue distribution.

3) Biological determinations that have been carried out on the donor and their results.

4) Storage recommendations.

5) Instructions for opening the container, for packaging and for any handling or reconstitution.

6) Expiration dates after container opening or handling.

7) Instructions for communication of effects or adverse reactions.

8) Presence of potentially hazardous waste (antibiotics, ethylene oxide, etc.).

iii) External labeling for the shipping or shipping container.

For shipment, the primary container must be included in a properly labeled shipping container. This tag will contain at least the following information:

1) Identification of establishment of source tissues, including address, telephone, and contact person.

2) Identification of tissue implant center or target tissue establishment, including address, telephone, and contact person.

3) The finding that the package contains human tissues or cells and that it should be handled with care.

4) If live cells are sent and the maintenance of viability is essential for the success of the graft, as is the case with haematopoietic progenitors, precursor cells, gametes or embryonic cells, it should be added in one place. The announcement of "NOT IRRADAR" is visible.

5) Recommendations for transport conditions (position, temperature etc).

6) Safety instructions.

7) Methods of freezing or defrosting or any other necessary manipulation where applicable.

4. The specific requirements for eligibility as centres, or human tissue implantation units, according to the activity to be developed, are:

a) Activities for the implantation of haematopoietic progenitors, including the implantation of hematopoietic precursors from bone marrow, peripheral blood, umbilical cord, or others.

1. º are established as specific minimum requirements common to the centers to obtain authorization for the three types of transplant mentioned, the following:

1) Displacement of specialist staff with proven experience in bone marrow transplantation.

2) Ensure the availability of a physician with proven experience in the diagnosis and treatment of bone marrow transplant complications.

3) Dispose of nursing staff with training in this type of care.

4) Being equipped with an Intensive Care Unit, an Image Diagnostic Service with the availability of appropriate techniques and appropriate general laboratories.

5) Dispose of an appropriate anti-infectious isolation area.

6) Contar with a Service or Unit of Hematologia-Hemotherapy or Blood Bank, which will be responsible for the appropriate hemoterapic support, mechanized cytoapheresis and obtaining, cryopreservation and storage of the haematopoietic progenitors.

7) Dispose of a Service or Unit of Pharmacy and/or Trained Nutrition for the elaboration of solutions for enteric or parenteral nutrition adjusted to the situation of the patients.

8) To be equipped with a Pathological Anatomy Laboratory that has the technical and human means necessary for the diagnosis of the complications associated with the transplant and to be able to carry out the possible post-mortem studies.

9) Dispose of a Microbiology Laboratory where the controls of infectious complications presented by patients can be carried out.

2. In this group of activities and depending on the different types of transplantation for which authorization is sought, the centers will have to comply, in addition to all the preceding requirements, the following:

1) The approval of allogeneic transplant centres will be subject to a minimum number of annual procedures to be determined by the Council's Commission on Transplant and Regenerative Medicine. Interterritorial of the National Health System.

2) For the realization of allogeneic implants from family donors, the center must meet, in addition to the specific and the specific requirements mentioned in the previous section, the following:

i) Dispose of a histocompatibility, own or concerted laboratory, capable of determining the polymorphism of the main histocompatibility complex (MHC, HLA) for loci A, B, C, DR and DQ at low or high resolution.

ii) Dispose of an isolation area that at least applies an inverted isolation system.

3) For the realization of allogeneic implants from non-related donors the center, in addition to the above requirements (autoimplants and bone marrow implant from family donors) should guarantee the availability of a Histocompatibility Laboratory capable of determining the loci A, B, C, DRB1 and DQ by high resolution DNA.

b) Oste-tendinous tissue implant activities: having a specialized Surgical Unit with at least one experienced specialist in such transplants.

c) Skin implant activities: have a specialized Surgical Unit with at least one specialist with proven skin transplant experience.

d) Heart valve implant activities: having a specialized surgery unit, with extensive and recognized experience in interventions with extracorporeal circulation, as well as, at least, a professional with proven experience in the implantation of valves.

e) vascular segment implant activities: having a Surgery Unit with at least one specialist with experience in such transplants.

f) Eye tissue implant activities, including corneas, limbocorneal, sclera, and other ocular tissues: having a specialized Surgery Unit with at least one specialist with experience in such transplants.

g) Implants of cell groups: have the necessary unit and equipment to carry out the specific implants in question.

ANNEX II

Clinical requirements for the assessment of tissue and cell donors

1. Deceased donors.

1.1 General exclusion criteria: In general, potential donors who meet any of the following criteria will not be considered as valid donors:

a) Cause of unknown death, except in cases where an autopsy may be performed and that it demonstrates that no reason for exclusion is found on the corpse.

b) History of unaffiliated disease.

c) Ing or exposure to any toxic that can be transmitted, at toxic doses, to the receptor through tissues or cells (cyanide, lead, mercury, gold, etc.).

d) Presence or history of malignant disease, except primary basal cell carcinoma, in situ carcinoma of uterine cervix, and some of the primary tumors of the central nervous system in which scientific evidence says that the risk of transmission is acceptable from the point of view of safety and quality. Donors with malignant diseases may be accepted as corneal donors, except in cases of retinoblastoma, haematological malignancies, and other malignant tumors that may affect the anterior pole of the eye.

e) Risk of presenting diseases caused by prions. This risk includes the following examples:

1. No diagnosis of Creutzfeld-Jakob disease or variant Creutzfeld-Jakob disease or family history of Creutzfeld-Jakob disease-non-iatrogenic disease.

2. History of rapidly progressive dementia or degenerative neurological disease of unknown origin.

3. Previous treatment with hormones derived from the pituitary gland (i.e. growth hormone). Dura, corneal or sclera receptors. Persons subject to non-documented surgical intervention where the duration of the operation may have been used.

f) Active and uncontrolled infection at the time of donation, including bacterial infection and parasitic or fungal viral systemic infection, or localized infection in the tissues to be used. Potential donors with bacterial sepsis may be evaluated and considered for corneas extraction if they are to be stored in crops that allow for the detection of bacterial contamination.

g) History, existence of risk factors for transmission, clinical evidence or laboratory tests positive for HIV, hepatitis B, hepatitis C and HTLV I and II.

h) History of chronic autoimmune disease that may have damaged the tissues to be used.

i) Presence of other risk factors for disease transmission, taking into account travel history and local prevalence of infectious diseases.

j) Risk that biological tests may be invalidated:

1. º For the existence of hemodilution (see Annex III).

2. º By treatment with immunosuppressants.

k) Presence of physical signs that may pose a risk of disease transmission.

l) Recent history of vaccination with attenuated viruses, which may constitute a source of contagion.

m) Xenotransplantation receptors.

1.2 Specific exclusion criteria for the paediatric age: In addition to what is specified in the previous point, which is equally applicable to paediatric donors, any child born to a mother carrying or suffering from HIV or which may be included within the paragraphs of the previous point, must be excluded, unless it can be demonstrated that there is no risk of transmission:

a) Donors under 18 months of age born to mothers with positive markers of HIV, hepatitis B or C or who have risk factors for these diseases, who have received breast-feeding in the previous 12 months should be discarded independently of serological tests.

b) Donors under 18 months of age born to mothers with positive HIV, hepatitis B or C markers who have not received breast-feeding in the previous 12 months and who have no clinical evidence or history compatible with infected status, whose serological tests are negative for HIV, hepatitis B or C can be accepted as donors.

1.3 External physical examination. -Detailed physical examination of the body should be performed to detect signs that may indicate that there is a risk of disease transmission: tumors (i.e. melanoma), infections (i.e. genital ulcers or anal conditions), risk factors for transmission of infectious disease (signs of venipuncture, tattoos or unaffiliated piercings).

2. Living donor.

2.1 Autologous Living Donor: The physician responsible for the therapeutic procedure should determine, on the basis of the medical history, the therapeutic indication and the documentation available, the justification for the donation and the security criteria.

If the cells or tissues obtained are to be stored, cultivated or subjected to some "ex vivo" transformation process, the same biological tests will be performed as those required for allogeneic donors. The positive results of any of the tests shall not prevent the reimplantation of the cells, tissues or derived products.

Both the patient or his legal representative and the responsible physician must sign the donation document in accordance with the current legal provisions and the provisions of Article 7. In this document, the patient must acknowledge that the information he has provided is consistent with his or her knowledge margin.

2.2 Allogeneic Living Donor: The donor will be selected based on the knowledge of his/her medical history and the personal interview conducted by the responsible medical professional. This evaluation will include those points that are relevant in identifying and selecting potential donors whose donation could pose a risk to third-party health, such as the possibility of disease transmission, or own health. In the case of donation of umbilical cord blood or amniotic membrane, there should be no interference or commitment to the care and safety of the mother or newborn.

The criteria for the selection of live donor tissues or cells for allogeneic use shall be established and documented in the establishment of tissues to be received, or in the transplantation unit, in the case of a direct reference of the cells or tissues of the procurement centre to the implant. These criteria will include the specific of each tissue or cell group plus those that refer to the general state of the donor, its clinical history and social habits, and the results of clinical and laboratory examination tests. designated to verify the donor's health status.

The same general exclusion criteria that have been specified for deceased donors will be followed. In selected cases of transplantation of haematopoietic progenitors, donors with positive B and C viral markers may be admitted. In cases of gametes donation within the couple, the criteria specified for this purpose will be followed (according to Annex IV).

Other exclusion criteria will be added to the cell or cell group:

a) Pregnancy: Except for the donation of haematopoietic progenitors and amniotic membrane.

b) Breast-feeding.

c) The possibility of transmitting hereditary diseases in the case of haematopoietic progenitors and gametes.

Both the donor or his legal representative and the responsible physician must sign the donation document in accordance with the current legal provisions and the provisions of Article 7. In such a document, the donor must acknowledge that the information he has provided is consistent with his or her margin of knowledge.

ANNEX III

Laboratory tests required in donor assessment (except reproductive cell donors)

1. Biological tests required for donors.

1.1 The following tests will be required at least in all cases of cell and tissue donation:

HIV 1 and 2: Anti-HIV-1 Antibodies, 2.

Hepatitis B: HBs Ag. Anti. Hbc.

Hepatitis C: AntiHVC Antibodies (in cases of haematopoietic progenitors will be further required PCR).

Syphilis: View 1.4.

1.2 Anti HTLV I and II antibody tests must be performed on donors who live or come from areas with a high incidence of the disease. They will also be performed on donors who are sexual partners or children of people living or coming from areas with high incidence of the disease.

1.3 When the anti-HB-C antibody test is positive and the HBsAg negative, additional tests will be required to determine whether the tissues and/or cells can be used or should be discarded.

1.4 Additional tests will be performed in some circumstances depending on the donor's history or the characteristics of the cells or tissue to be used (CMV, T. cruzi, toxoplasma, malaria, Dengue, VEB, HLA, RhD).

1.5 A diagnostic algorithm will be applied to exclude the presence of active infection with Treponema Pallidum:

a) Non-reactive test, specific or not: allows the use of tissues or cells.

b) Non-specific reagent test: a specific test should be performed which, if not reactive, will allow the use of tissues or cells.

c) Reactive specific test: A specific risk assessment is required to determine the use or not of the cells and/or tissues.

1.6 For autologous donors, account shall be taken of the requirements set out in Annex II, paragraph

.

2. General requirements for biological tests.

2.1 The tests shall be carried out in laboratories qualified and approved by the competent authorities of the relevant autonomous community. CE marked kits shall be used when available on the market. The type of test used must be validated for the purpose it pursues, according to scientific knowledge and following the manufacturer's instructions.

2.2 Biological tests will be performed on the donor's serum or plasma. They should not be performed in other fluids, such as vitreous or aqueous humour, unless specifically justified.

2.3 When deceased donors have received blood transfusions or blood components and/or colloids in the 48 hours preceding death or crystalloids in the time preceding death, the the algorithm for the calculation of hemodilution. Tissue establishments may accept tissues or cells from donors with hemodilution rates of more than 50%, only if the laboratory test is validated for blood samples or any plasma or serum sample is found prior to transfusions/infusions.

a) "Post-mortem" blood samples: if blood components, blood or colloids have been infused in the 48 hours preceding the sampling or crystalloids in the preceding hour.

b) "post-mortem" blood samples: if blood components, blood or colloids have been infused in the 48 hours preceding death or crystalloids in the hour preceding death.

2.4 In the case of deceased donors, blood samples must be obtained before death. If not, the samples shall be obtained as soon as possible and, in any case, before 24 hours after the death.

2.5 Other assumptions:

(a) In the case of living donors (except for bone marrow progenitor cells and peripheral blood progenitor cells, for practical reasons), blood samples for serology should be obtained at the time of the donation or within the margin of 7 days following the donation (from 0 to + 7).

(b) When cells and/or tissues are to be stored for long periods, a second determination shall be required at 180 days. In these cases the "donation sample" may be taken in the interval between the previous 7 days and the 30 days after the donation (from − 7 to + 30).

(c) Where the cells and/or tissues of an allogeneic donor are not to be stored for long periods and the second determination cannot be carried out, point (a) shall apply.

2.6 If DNA amplification techniques are applied for the determination of the presence of HIV, HBV and HLV, a second determination will not be required. It will also not be necessary if any validated process of viral inactivation is included during the processing phase of the tissue and/or cell group.

2.7 In the case of allogeneic donors of hematopoietic progenitors blood samples will be analyzed within the 30-day margin pre-extraction.

2.8 In the case of hematopoietic progenitors of umbilical cord blood, the blood of the mother and the blood of the cord will be analyzed.

2.9 In the case of neonates, the sample will be obtained from the mother to avoid unnecessary medical procedures for the child.

ANNEX IV

Selecting and evaluating the donor of reproductive cells

1. Donation between members of the couple for direct use.

The clinical or laboratory evaluation criteria shall not apply to cases of reproductive cell donation between members of a partner for direct use.

2. Donation between members of the couple for deferred use.

When the reproductive cells are to be stored or processed, the following criteria must be met:

2.1 The physician responsible for the gamete donation process must determine and document, on the basis of the medical history and the therapeutic indication, the justification for obtaining and the safety criteria for the mother and children that could result from the process.

2.2 The following serological tests will be performed to assess the risk of cross-contamination:

HIV 1 and 2: Anti-HIV-1 Antibodies, 2.

Hepatitis B: Antigen HBs/Anti HBC Antibodies.

Hepatitis C: Anti-HCV Antibodies.

When the results of tests for HIV 1 and 2 or Hepatitis B or C are positive or are not available, or when the donor is known to have some risk factor for transmission of these infections, a isolated storage system.

2.3 Anti-HTLV I and II antibody determination tests will be performed on donors who live or come from areas with a high incidence of disease or whose sexual partners or parents come or live in areas of high blood. incidence of disease.

2.4 Additional tests (malaria, toxoplasma, Tripanosoma cruzi, Dengue, CMV, VEB, RhD) will be required in some circumstances depending on the existence of travel, or exposure to contagion, or the characteristics of the cells obtained.

2.5 The fact that tests are positive does not necessarily prevent the use of the obtained cells, or derived products, in cases of donation between people of the same partner, always according to the rules in effect.

2.6 When the HIV 1 and 2 or hepatitis B or C test are positive or the results are not available, or if the donor presents any risk criteria for infection, an isolated storage system will be used.

3. Donations outside the couple.

The use of donor cells from different donors to the usual partner must meet the following criteria:

a) Donors will be selected on the basis of their clinical history, which should be made by the responsible practitioner. This assessment shall include any factors that may be relevant to the identification and selection of persons whose donation may pose a risk to third-party health, such as the possibility of transmitting a disease, or (i.e. induction and/or stimulation of ovulation, sedation, risks associated with the removal of eggs or psychological consequences).

b) Donors should have negative serological markers for HIV 1 and 2, HVC and HVB and syphilis. Sperm donors must also have negative markers for chlamydia in a urine sample and by determination by PCR.

c) Tests for the determination of anti-HTLV I and II antibodies in donors who live or come from areas with high incidence of disease or whose sexual partners or progenitors live or come from areas with high incidence of the disease.

d) In some circumstances additional tests will be required depending on the donor's medical history or the characteristics of the cells or tissues (i.e. malaria -CMV-Tripanosoma cruzi, RhD).

e) In the case of autologous donations, the provisions set out in Annex II, paragraph 2.1. shall apply.

f) A genetic load assessment shall be carried out in relation to the existence of recessive autonomic genes according to scientific knowledge and the known prevalence in the donor's ethnicity.

g) An assessment of the risk of transmission of hereditary diseases known and present in the family will be carried out. The participants shall be informed of the results obtained in accordance with the provisions of Law 41/2002 of 14 November, basic regulation of the autonomy of the patient and of rights and obligations in relation to the information and clinical documentation and Law 14/2006 of 26 May on techniques for assisted human reproduction. This information shall be as complete as possible in relation to the associated risks and the measures taken or to be taken, and should be clearly transmitted and explained to the recipient.

h) Basic requirements for the conduct of biological tests.

The biological tests shall be carried out in accordance with the requirements of paragraph 3.2 of Annex III:

1. º Blood samples will be obtained at the time of donation.

2. The sperm samples shall be kept in quarantine for at least 180 days, after which the biological tests shall be repeated. This second assessment can be avoided if the first determination was made by means of nucleic acid amplification testing. Likewise, the second determination of biological tests can be avoided if in the process of transformation or subsequent management the cells will undergo a validated process of viral inactivation.

ANNEX V

Donation, cell and tissue extraction procedures and their reception in tissue establishment

1. Donation and extraction.

1.1 Confeeling and identification of the donor. -Before proceeding to the removal of the cells and tissues, the person responsible for the procedure or person authorized to do so must confirm and register:

(a) That the consent for the extraction has been obtained in accordance with the legislation in force.

b) How the donor was identified.

c) That, in the case of live donations, the donor has understood the information provided, has had the opportunity to ask questions and has obtained satisfactory answers and has confirmed that the information it has provided facilitated, with respect to your clinical history, is true to where your knowledge comes.

1.2 Donor Assessment.

1.2.1 The person responsible for the extraction procedure or person authorised to do so must collect and record all the clinical and social information of the donor that is relevant to the assessment as described in the paragraph 1.4 of this Annex (donor documentation).

1.2.2 In the case of living donors, a personal interview will be conducted during which a structured questionnaire will be completed. In the case of deceased donors the questionnaire will be filled with the help of:

a) The family or those close to them (social and habit anamnesis).

b) The doctor who has treated you.

c) Your GP (if applicable).

d) The medical history/autopsy results.

1.2.3 A physical examination of the donor will be carried out to detect any signs or marks that may be suspected of disease transmission or are complementary to the information in the medical history and may be require additional assessments before accepting the donor: tumours (melanomas), infections (genital ulcers or anal conditions), risk factors for communicable diseases (venopuntions), trauma or scarring of operations recent or old.

1.3 Removing cells and tissues.

1.3.1 The extraction procedures shall be suitable for the type of donor and the type of cells or tissues to be obtained, as well as to ensure the protection of the donor.

1.3.2 The procedures used should ensure that the properties of these cells or tissues that are required for clinical use are protected and that the risks of microbiological contamination are minimised, especially if the Cells or tissues are not intended for subsequent sterilization treatment.

1.3.3 In the case of deceased donors, the site of the extraction should be recorded (or described in the extraction report) which should be a restricted area. The medical equipment to be extracted must take the most appropriate preventive measures for contamination in each case. In general, this should include washing the work surfaces with antiseptic solutions, preparing a sterile field, performing a surgical wash of hands and using sterile gloves and gowns, as well as mask and cap.

1.3.4 In the case of missing donor extractions, the time of death and the time of removal should be recorded, the interval being recorded and ensuring that the limits guaranteeing that they are preserved are not exceeded. the biological characteristics and properties of the cells and tissues.

1.3.5 Once the tissues or cell groups of a deceased donor have been removed, a reconstruction of the affected areas will be carried out in such a way that it is as close as possible to their prior anatomical appearance.

1.3.6 Any events occurring during the extraction procedure and which may result or have been detrimental to the donor, as well as any further investigation arising from these facts to determine their cause, must be properly collected and evaluated.

1.3.7 There should be standardized procedure guides available to minimize the risk of contamination by staff members who may be infected with communicable diseases.

1.3.8 For the removal of cells and tissues, high quality, validated and/or specifically certified and/or certified sterile instruments and systems shall be used regularly for the use to which they are intended.

1.3.9 When multi-use instruments are used, validated standardized procedures must be available for the cleaning and sterilisation of such material.

1.3.10 Whenever possible, EU certification materials will be used and the staff involved in the handling of such equipment will be trained appropriately.

1.4 Donor documentation.

1.4.1 For each donor a file must be prepared containing:

a) Identification of the donor (name, last name and date of birth with its identifying equivalent).

(b) In the case of donations of neonates or cord blood or any other tissue or cell group obtained at the time of delivery, the mother's name and date of birth shall be recorded, the date of birth of the donor and her name if known.

c) Sex, age, medical and social history.

d) Summary of physical scan.

e) Formula of the hemodilution calculation (if applicable).

f) The consent document for the procurement.

g) Clinical data, results of laboratory tests and any other tests or tests performed.

h) The result of the report if a necropsic test has been performed.

i) In the case of haematopoietic progenitors, the documentation concerning the suitability of the donor for a given recipient shall be recorded.

1.4.2 The extraction team will produce a report of the extraction procedure from which a copy will be sent to the tissue processing establishment. This report will contain at least the following information:

a) Identification, name and address of the target establishment to receive the cell group and/or extracted tissues.

b) Identification of the donor, including how identification has been carried out and who did it.

c) Cause, date and time of death (in deceased donor).

d) Description and identification of the extracted tissues and cells and the samples obtained for evaluation.

e) Identification of the manager of the extraction and signature group of the group.

f) Date and time (start and end), place of extraction and procedure used (POE, if applicable). Description of the area and the conditions in which the extraction was performed (if applicable).

g) Incidents occurred during extraction.

h) In the case of deceased donors, information on the methods and conditions of carcass conservation: whether or not it has been refrigerated, temperature, time, start and end of refrigeration.

i) Reassets and conservation solutions used (Batch identification).

j) In the case of sperm donors the minimum information to be reported shall be:

1. The name of the target tissue establishment.

2. The donor identification data.

3. Date and time of the get.

k) The information relating to the donor must be archived and protected against unauthorised modifications, which are properly and accessible to the competent authority, at least up to 30 years after clinical use or expiry of the obtained cells or tissues.

1.5 Packaging.

1.5.1 After removal all cells and tissues shall be packaged in such a way as to minimise the risks of contamination and to ensure the required temperature to preserve biological characteristics and properties, and functional cells and tissues. In addition, packaging should prevent contamination by those who carry it out and who transport the tissues and cells.

1.5.2 Packaged cells and tissues must be transported in containers suitable for the transport of biological material and maintain their quality and safety.

1.5.3 The samples of tissue or blood accompanying those obtained for ultimate use in order to serve for further tests or analytical determinations shall be appropriately labelled. The identification of the donor and the information concerning the place and the time when the specimen was collected should be included in these labels.

1.6 Labelling of the extracted tissues or cells.

1.6.1 In the internal containers of cells and/or tissues for human use, a label containing at least the following information must appear:

a) Donor identification code.

b) Type of cell and/or fabric.

1.6.2 If the container so permits, by virtue of its dimensions, it must also be shown:

a) Date and time of the get.

b) Precautions (if applicable).

c) Additives used (if applicable).

d) In case of direct donations the receiver must be identified.

e) In the case of autologous donations, it must be stated: "Only for autologous use".

1.7 Labelling of the external transport container. -In the transport container of the cells and/or tissues a label must appear where the following information is specified:

a) "Biological sample of cells/weaves-Handle with care".

b) Identification of tissue establishment of tissue and/or cell group, including address and telephone and contact person for any contingency.

c) Identification of target tissue establishment, including address and telephone, as well as the contact person to be delivered to the container.

d) The date and time of the transport start.

e) Specifications to maintain the biological characteristics of cells or tissues during transport (if applicable).

f) Storage specifications if applicable (i.e. NOT FREEZE).

g) In case the tissues or cells may be affected by X-rays, it should be clearly "NOT IRRADAR".

h) In cases of products known to be potentially polluting or of which the results of serological tests are not known, it should be specified: "RISK OF BIOLOGICAL CONTAMINATION".

i) In the case of autologous donations, it must be clearly stated "For autologous use only".

2. Reception of tissue and/or cell group in tissue establishment.

2.1 General Conditions.-When the extracted tissue and/or cell group reaches the tissue establishment, a documented verification procedure will be performed that the received consignment meets all the requirements required, both in this royal decree and in the specifications of the tissue establishment itself, in relation to the conditions of transport, packaging and labelling, and in relation to the samples for further controls and information and documentation to accompany tissues and/or cells.

The tissue establishment must ensure that the tissues and/or cells received remain in quarantine until they themselves and all accompanying documentation has been the subject of the analyses, controls, inspections or checks required in this royal decree-law and in the specifications of the establishment itself. The review of the documentation, as well as the subsequent decision on its acceptance, should be made by the person authorized or designated in the tissue establishment.

Each tissue establishment must have a documented procedure to ensure that shipments of received tissues and/or cells that do not meet the requirements set, or whose documentation is incomplete or that are expects to complete the results of the donor assessment, are stored so that there is no risk of contamination for other tissues and/or cells preserved, stored or processed in the same establishment.

2.2 Data recording. -Data to be recorded in the tissue establishment (except in the case of donation of reproductive cells between members of the couple) shall be at least the following:

a) Consent or authorization for the extraction, where the purpose of use (therapeutic use or research or both) is recorded and any specific instructions for destruction when not used for the purpose purpose with which they were obtained.

(b) Those relating to the identification of the donor and its characteristics, including the type of donor and the cause of death, if appropriate, as described in the section: "Documentation".

(c) Those relating to the donor's medical history and the extraction procedure, as outlined in the relevant Annex.

(d) Those relating to the physical examination of the donor, the results of laboratory tests or any other test performed on the donor, including those of the necropsy in case of having been performed.

e) The complete donor assessment report signed by the responsible for the assessment and selection process or authorized person.

(f) Those relating to the extraction procedure, as set out in the relevant annex, including the place of removal and the person responsible.

g) The tissues and/or cells that are received and their characteristics.

h) In case of autologous fabric, you must also specify:

1. The characteristics of the injury or pathological process to be treated.

2. Drug allergies or products that can be used in conservation and processing.

2.2.1 In the case of cell cultures for autologous use, the information on possible allergies of the recipient (i.e. antibiotics) will also be reported.

2.2.2 In the case of donations from breeding cells outside the usual partner, the following data relating to donors shall be included: size, weight, race, skin colour (pale, brown), eye colour (brown, green, amber, blue, black), hair color (blond, light brown, dark brown, redhead, black), hair texture (smooth, wavy, curly), blood group and Rh.

2.2.3 In the case of reproductive cells that are to be used within the usual partner, the data to be reported are:

a) Consent/authorization for the extraction, where the purpose of use is consigned (therapeutic use/research or both) and any specific instructions for their destruction when not used for the purpose with which they were obtained.

b) Donor identification data: type of donor, age, gender, presence of risk factors and cause of death in case of deceased donors.

c) Identification data of the couple: age, gender and presence of risk factors.

d) Place of cell group procurement.

e) Cells or tissues obtained and their most relevant characteristics.

3. Requirements for direct distribution to the tissue implant center and/or specific cells.

Exceptionally the Transplant Autonomous Coordination Unit and/or the National Transplant Organisation may authorise the direct dispatch of certain specific cells or tissues from the centre where the extraction is carried out. to the implant center for immediate use. (i.e. haematopoietic progenitor cells, corneas, etc.). In any event, the requirements specified in these Annexes shall be required for the identification, extraction, packaging, shipping, preservation and labelling.

ANNEX VI

Minimum information required in the traceability system of origin to target cells and human tissues obtained for human application

1. Information to be saved and guarded by tissue establishment:

a) Identification of the approved procurement centre, unit or body.

b) Unique identification number of donation.

c) Get date.

d) Place to get.

e) Donation/Get Type:

1. Deceased-Vivo.

2. MultiFabric -Tejid/single cell group.

3. Alogenic-Autolog.

f) Identification of tissue establishment.

g) Type of tissue or cell group.

h) Batch number, if applicable.

i) Subpartition number, if applicable.

j) Expiration date.

k) tissue status/cell group:

1. Available.

2. Descarted.

3. Quarantine.

l) Description of the product, cells or tissue: origin, processing or processing phases applied, materials and additives which have been or are in contact with the cells or tissues and which may affect their quality and/or security or whose presence should be taken into account for security reasons for the persons in which they are applied (ie. presence of antibiotics and possible allergic reactions).

m) Internal and external tissue or cell group labeling.

n) Date of availability.

n) Identification of the application center or unit.

2. Information to be saved and guarded by the application center or unit:

a) Identification of the vendor fabric establishment.

b) Identification of the unit or application center responsible.

c) Type of tissue/cell group.

d) Identification of the product.

e) Identification of the recipient or person in which the tissue or cell group is applied.

f) Date of use, application, or otherwise discard and cause of non-use in the latter case.

ANNEX VII

Cell and tissue coding system

1. Information contained:

1. Identification of the donation:

a) Identification of the donation.

b) Identification of tissue establishment.

2. Product identification:

a) Basic product code.

b) Partition number.

c) Expiration date.

ANNEX VIII

Biosurveillance System