TISSUES AND CELLS (QUALITY AND SAFETY) REGULATIONS

SUBSIDIARY LEGISLATION 483.01

TISSUES AND CELLS

(QUALITY AND SAFETY) REGULATIONS

10th November, 2006

LEGAL NOTICE 271 of 2006, as amended by Legal Notice 222 of 2014.

(1) The title of these regulations is the Tissues and Cells

(Quality and Safety) Regulations.

(2) The scope of these regulations is to transpose Directive

2004/23/EC of the European Parliament and of the Council of 31

March 2004 on setting standards of quality and safety for the

donation, procurement, testing, processing, preservation, storage

and distribution of human tissues and cells, and Directive 2006/17/

EC of the European Parliament and of the Council of the 8th

February 2006 as regards certain technical requirements for the

donation, procurement and testing of human tissues and cells.

(3) The scope of these regulations is also to transpose

Commission Directive 2012/39/EU of 26 November 2012 amending

Directive 2006/17/EC as regards certain technical requirements for the

testing of human tissues and cells.

Information to be provided on the Donation

of Cells and/or Tissues

A.

Living donors

1. The person in charge of the donation process shall ensure

that the donor has been properly informed of at least those aspects

relating to the donation and procurement process outlined in

paragraph 3. Information must be given prior to the procurement.

2. The information must be given by a trained person able to

transmit it in an appropriate and clear manner, using terms that are

easily understood by the donor.

3. The information must cover: the purpose and nature of the

procurement, its consequences and risks; analytical tests, if they are

performed; recording and protection of donor data, medical

confidentiality; therapeutic purpose and potential benefits and

information on the applicable safeguards intended to protect the

donor.

4. The donor must be informed that he/she has the right to

receive the confirmed results of the analytical tests, clearly

explained.

5. Information must be given on the necessity for requiring

the applicable mandatory consent, certification and authorisation in

order that the tissue and/or cell procurement can be carried out.

B.

Deceased donors

1. All information must be given and all necessary consents

and authorisations must be obtained in accordance with the

National legislation in force.

2. The confirmed results of the donor's evaluation must be

communicated and clearly explained to the relevant persons in

accordance with the relevant national legislation.

In these regulations unless the context otherwise requires

"the Act" means the Human Blood and Transplants Act;

"allogeneic use" means cells or tissues removed from one person

and applied to another;

"autologous use" means cells or tissues removed from and

applied in the same person;

"cells" means individual human cells or a collection of human

cells when not bound by any form of connective tissue;

"Directive 2004/23/EC" means the Dirctive of the European

Parliament and of the Council of 31 March 2004 on setting

standards of quality and safety for the donation, procurement,

testing, processing, preservation, storage and distribution of human

tissues and cells;

"Directive 2006/17/EC" means the Directive of the European

Parliament and of the Council of the 8th February 2006 as regards

certain technical requirements for the donation, procurement and

testing of human tissues and cells as amended by Commission

Directive 2012/39/EU of 26 November 2012 amending Directive

2006/17/EC as regards certain technical requirements for the

testing of human tissues and cells;

"direct use" means any procedure where cells are donated and

used without any banking;

"distribution" means transportation and delivery of tissues or

cells intended for human applications;

"donation" means donating human tissues or cells intended for

human applications;

"donor" means every human source, whether living or deceased,

of human cells or tissues;

"human application" means the use of tissues or cells on or in a

human recipient and extracorporal applications;

"organ" means a differentiated and vital part of the human body,

formed by different tissues, that maintains its structure,

vascularisation and capacity to develop physiological functions

with an important level of autonomy;

"partner donation" means the donation of reproductive cells

between a man and a woman who declare that they have an intimate

physical relationship;

"preservation" means the use of chemical agents, alterations in

environmental conditions or other means during processing to

prevent or retard biological or physical deterioration of cells or

tissues;

"processing" means all operations involved in the preparation,

manipulation, preservation and packaging of tissues or cells

intended for human applications;

"procurement" means a process by which tissue or cells are made

available;

"procurement organisation" means a health care establishment or

a unit of a hospital or another body that undertakes the procurement

of hum an tissues and cells and that may not be accredited,

designated, authorised or licensed as a tissue establishment;

"quality system" means the organisational structure, defined

responsibilities, procedures, processes, and resources for

implementing quality management and includes all activities which

contribute to quality, directly or indirectly;

"quarantine" means the status of retrieved tissue or cells, or

tissue isolated physically or by other effective means, whilst

awaiting a decision on their acceptance or rejection;

"reproductive cells" means all tissues and cells intended to be

used for the purpose of assisted reproduction;

" s e r i o u s a d v e r s e e v e n t " m e a n s an y u n t o wa r d o c c u r r e n c e

associated with the procurement, testing, processing, storage and

distribution of tissues and cells that might lead to the transmission

of a communicable disease, to death or life-threatening, disabling

or incapacitating conditions for patients or which might result in, or

prolong, hospitalisation or morbidity;

"serious adverse reaction" means an unintended response,

including a communicable disease, in the donor or in the recipient

associated with the procurement or human application of tissues

and cells that is fatal, life-threatening, disabling, incapacitating or

which results in, or prolongs, hospitalisation or morbidity;

"standard operating procedures" (SOPs) means written

instructions describing the steps in a specific process, including the

materials and methods to be used and the expected end product;

"storage" means maintaining the product under appropriate

controlled conditions until distribution;

"tissue" means all constituent parts of the human body formed by

cells;

"tissue establishment" means a tissue bank or a unit of a hospital

or another body where activities of processing, preservation,

storage or distribution of human tissues and cells are undertaken. It

may also be responsible for procurement or testing of tissues and

cells;

"traceability" means the ability to locate and identify the tissue

or cell during any step from procurement, through processing,

testing and storage, to distribution to the recipient or disposal,

which also implies the ability to identify the donor and the tissue

establishment or the manufacturing facility receiving, processing or

storing the tissue or cells, and the ability to identify any recipient at

the medical facility or facilities applying the tissue or cells to any

recipient< traceability also covers the ability to locate and identify

all relevant data relating to products and materials coming into

contact with those tissues or cells;

"validation" (or "qualification" in the case of equipment or

environments) means establishing documented evidence that

provides a high degree of assurance that a specific process, SOP,

piece of equipment or environment will consistently produce a

product meeting its predetermined specifications and quality

attributes; a process is validated to evaluate the performance of a

system with regard to its effectiveness based on intended use.

Selection Criteria for Donors of Tissues and/or Cells

(except Donors of Reproductive Cells)

as referred to in paragraph (a) of regulation 13.

Selection criteria for donors are based on an analysis of the risks

related to the application of the specific cells/tissues.

Indicators of these risks must be identified by physical

examination, review of the medical and behavioural history,

biological testing, post-mortem examination (for deceased donors)

and any other appropriate investigation. Unless justified on the

basis of a documented risk assessment approved by the responsible

person as defined in regulation 3, donors must be excluded from

donation if any of the following criteria applies

1. Deceased Donors

1.1.

General criteria for exclusion

1.1.1. Cause of death unknown, unless autopsy provides

information on the cause of death after procurement and none of

the general criteria for exclusion set out in the present section

applies.

1.1.2. History of a disease of unknown aetiology.

1.1.3. Presence, or previous history, of malignant disease,

except for primary basal cell carcinoma, carcinoma in situ of the

uterine cervix, and some primary tumours of the central nervous

system that have to be evaluated according to scientific evidence.

Donors with malignant diseases can be evaluated and considered

for cornea donation, e xcept for t ho se wi th r etin ob last om a,

haematological neoplasm, and malignant tumours of the anterior

segment of the eye.

1.1.4. Risk of transmission of diseases caused by prions. This

risk applies, for example, to

(a) people diagnosed with Creutzfeldt-Jakob disease, or

variant Creutzfeldt-Jacob disease, or having a family

history of non-iatrogenic Creutzfeldt-Jakob disease;

(b) people with a history of rapid progressive dementia or

degenerative neurological disease, including those of

unknown origin;

(c) recipients of hormones derived from the human

pituitary gland (such as growth hormones) and

recipients of grafts of cornea, sclera and dura mater,

and persons that have undergone undocumented

neurosurgery (where dura mater may have been used).

For

variant

Creutzfeldt-Jakob

disease,

further

precautionary measures may be recommended.

1.1.5. Systemic infection which is not controlled at the time of

donation, including bacterial diseases, systemic viral, fungal or

parasitic infections, or significant local infection in the tissues and

cells to be donated. Donors with bacterial septicaemia may be

evaluated and considered for eye donation but only where the

corneas are to be stored by organ culture to allow detection of any

bacterial contamination of the tissue.

1.1.6. History, clinical evidence, or laboratory evidence of HIV,

acute or chronic hepatitis B (except in the case of persons with a

proven immune status), hepatitis C and HTLV I/II, transmission

risk or evidence of risk factors for these infections.

1.1.7. History of chronic, systemic autoimmune disease that

could have a detrimental effect on the quality of the tissue to be

retrieved.

1.1.8. Indications that test results of donor blood samples will

be invalid due to

(a) the occurrence of haemodilution, according to the

specifications in Schedule III, section 2, where a pre-

transfusion sample is not available; or

(b) treatment with immunosuppressive agents.

1.1.9. Evidence of any other risk factors for transmissible

diseases on the basis of a risk assessment, taking into consideration

donor travel and exposure history and local infectious disease

prevalence.

1.1.10. Presence on the donor’s body of physical signs implying

a risk of transmissible disease(s) as described in Schedule V, point

1.2.3.

1.1.11. Ingestion of, or exposure to, a substance (such as

cyanide, lead, mercury, gold) that may be transmitted to recipients

in a dose that could endanger their health.

1.1.12. Recent history of vaccination with a live attenuated virus

where a risk of transmission is considered to exist.

1.1.13. Transplantation with xenografts.

1.2.

Additional exclusion criteria for deceased child donors

1.2.1. Any children born from mothers with HIV infection or

that meet any of the exclusion criteria described in section 1.1 must

be excluded as donors until the risk of transmission of infection can

be definitely ruled out.

(a) Children aged less than 18 months born from mothers

with HIV, hepatitis B, hepatitis C or HTLV infection,

or at risk of such infection, and who have been

breastfed by their mothers during the previous 12

months, cannot be considered as donors regardless of

the results of the analytical tests.

(b) Children of mothers with HIV, hepatitis B, hepatitis C

or HTLV infection, or at risk of such infection, and

who have not been breastfed by their mothers during

the previous 12 months and for whom analytical tests,

physical examinations, and reviews of medical records

do not provide evidence of HIV, hepatitis B, hepatitis

C or HTLV infection, can be accepted as donors.

2. Living donors

2.1.

Autologous living donor

2.1.1. If the removed tissues and cells are to be stored or

cultured, the same minimum set of biological testing requirements

must apply as for an allogeneic living donor. Positive test results

will not necessarily prevent the tissues or cells or any product

derived from them being stored, processed and reimplanted, if

appropriate isolated storage facilities are available to ensure no risk

o f cr o s s - c o n t a m i n a t i o n w i t h o t h e r g r a f t s a n d / o r n o r i s k o f

contamination with adventitious agents and/or mix-ups.

2.2.

Allogeneic living donor

2.2.1. Allogeneic living donors must be selected on the basis of

their health and medical history, provided on a questionnaire and

t hro ug h an i nt ervi ew pe rfo rm ed b y a qualified and trained

healthcare professional with the donor, in compliance with point

2.2.2. This assessment must include relevant factors that may assist

in identifying and screening out persons whose donation could

present a health risk to others, such as the possibility of

transmitting diseases or health risks to themselves. For any

do nation , t he collecti on process m ust no t int erfere with or

compromise the health or care of the donor. In the case of cord

blood or amniotic membrane donation, this applies to both mother

and baby.

2.2.2. Selection criteria for allogeneic living donors must be

established and documented by the tissue establishment (and the

transplanting clinician in the case of direct distribution to the

recipient), based on the specific tissue or cells to be donated,

t o g e t h e r w i t h t h e d o n o r ’s p h y s i c a l st a t u s a n d m e d i c a l a n d

behavioural history and the results of clinical investigations and

laboratory tests establishing the donor’s state of health.

2.2.3. The same exclusion criteria must be applied as for

deceased donors with the exception of point 1.1.1. Depending on

the tissue or cell to be donated, other specific exclusion criteria

may need to be added, such as

(a) pregnancy (except for donors of umbilical cord blood

cells and amniotic membrane and sibling donors of

haematopoietic progenitors);

(b) breastfeeding;

(c) in the case of haematopoietic progenitor cells, the

potential for transmission of inherited conditions.

(1) A tissue and cell establishment, hereinafter referred to

as "establishment", shall designate a person who shall be

responsible for the following tasks

(a) ensuring that human tissues and cells intended for

human applications in the establishment for which that

person is responsible are procured, tested, processed,

stored and distributed in accordance with these

regulations and with the laws in force in Malta;

(b) providing information to the competent authority or

authorities as required in regulation 6;

(c) ensuring that appropriate control measures are in place

within the tissue establishment and implementing the

requirements of regulations 4, 5, 7, 8, 11, 12, 13, 14, 15

within the tissue establishment; and

(d) ensure that the Authority is notified of any serious

adverse events and reactions and is provided with a

report analysing the cause and the ensuing outcome.

(2) An establishment shall only designate a person as a

responsible person if such person is in possession of

(a) a diploma, certificate or other evidence of formal

qualifications in the field of medical or biological

sciences awarded on completion of a university course

of study or a course recognised as equivalent by the

Authority; and

(b) at least two yearsí practical experience in the relevant

fields.

(3) The responsible person may delegate any of the tasks

specified in sub-regulation (1) to other persons who shall be

qualified by training and experience to perform them.

(4) The establishments shall notify the Licensing Authority,

hereinafter referred to as "the Authority" of the name of any

persons to whom tasks have been delegated by the responsible

person and the specific tasks which have been delegated to such

persons.

(5) Where the responsible person or a person to whom tasks

have been delegated is permanently or temporarily replaced, the

establishment shall immediately provide the Authority with the

name of the replacement, details of his qualifications and the date

on which the replacement began his duties.

(6) If the Authority considers that the responsible person does

not meet the requirements of sub-regulation (2), it may serve a

notice to that effect on the establishment.

(7) If, within fourteen days of receiving a notice in accordance

with sub-regulation (6), a establishment is not able to demonstrate

to the reasonable satisfaction of the Authority that the responsible

person does meet the requirements of sub-regulation (2), the

establishment shall, without delay -

(a) relieve him of the duties of responsible person in

respect of the establishment;

(b) appoint a new responsible person in his place; and

(c) notify the Authority that it has appointed a new

responsible person and provide details of the name and

qualifications of the person appointed.

Laboratory Tests required for Donors (except Donors of

Reproductive Cells) as referred to in paragraph (a) of regulation

13.

1. Biological tests required for donors

1.1.

The following biological tests must be performed for all

donors as a minimum requirement

HIV 1 and 2

Anti-HIV-1,2

Hepatitis B

HBsAg

Anti HBc

Hepatitis C

Anti-HCV-Ab

Syphilis

See 1.4 (below)

1.2.

HTLV-I antibody testing must be performed for donors

living in, or originating from, high-prevalence areas or with sexual

partners originating from those areas or where the donor’s parents

originate from those areas.

1.3.

When anti-HBc is positive and HBsAg is negative,

further investigations are necessary with a risk assessment to

determine eligibility for clinical use.

1.4.

A validated testing algorithm must be applied to exclude

the presence of active infection with Treponema pallidum. A non-

reactive test, specific or non-specific, can allow tissues and cells to

be released. When a non-specific test is performed, a reactive result

will not prevent procurement or release if a specific Treponema

confirmatory test is non-reactive. A donor whose specimen tests

reactive on a Treponema-specific test will require a thorough risk

assessment to determine eligibility for clinical use.

1.5.

In certain circumstances, additional testing may be

required depending on the donor’s history and the characteristics of

the tissue or cells donated (e.g. RhD, HLA, malaria, CMV,

toxoplasma, EBV, Trypanosoma cruzi).

1.6.

For autologous donors, Schedule II, point 2.1.1, applies.

2. General requirements

to

be

met

for

determining

biological markers

2.1.

The tests must be carried out by a qualified laboratory,

authorised as a testing centre by the Licensing Authority, using EC-

marked testing kits where appropriate. The type of test used must

be validated for the purpose in accordance with current scientific

knowledge.

2.2.

The biological tests will be carried out on the donor’s

serum or plasma; they must not be performed on other fluids or

secretions such as the aqueous or vitreous humour unless

specifically justified clinically using a validated test for such a

fluid.

2.3.

When potential donors have lost blood and have recently

received donated blood, blood components, colloids or crystalloids,

blood testing may not be valid due to haemodilution of the sample.

An algorithm must be applied to assess the degree of haemodilution

in the following circumstances

(a) ante-mortem blood sampling: if blood, blood

components and/or colloids were infused in the 48

hours preceding blood sampling or if crystalloids were

infused in the hour preceding blood sampling;

(b) post-mortem blood sampling: if blood, blood

components and/or colloids were infused in the 48

hours preceding death or if crystalloids were infused in

the hour preceding death.

Tissue establishments may accept tissues and cells from

donors with plasma dilution of more than 50% only if the testing

p r o c e d u r e s u s e d a r e v a l i d a t e d f o r su c h pl a s m a o r i f a p r e -

transfusion sample is available.

2.4.

In the case of a deceased donor, blood samples must have

been obtained just prior to death or, if not possible, the time of

sampling must be as soon as possible after death and in any case

within 24 hours after death.

2.5. (a)

In the case of living donors (except allogeneic bone

marrow stem-cell and peripheral blood stem-cell

donors, for practical reasons), blood samples must be

obtained at the time of donation or, if not possible,

within seven days post donation (this is the ‘donation

sample’).

(b) Where tissues and cells of allogeneic living donors can

be stored for long periods, repeat sampling and testing

is required after an interval of 180 days. In these

circumstances of repeat testing, the donation sample

can be taken up to 30 days prior to and 7 days post

donation.

(c) Where tissues and cells of allogeneic living donors

cannot be stored for long periods and repeat sampling

is therefore not possible, point 2(5)(a) above applies.

2.6.

If in a living donor (except bone marrow stem-cell and

peripheral blood stem-cell donors) the ‘donation sample’, as

defined in point 2(5)(a) above, is additionally tested by the nucleic

acid amplification technique (NAT) for HIV, HBV and HCV,

testing of a repeat blood sample is not required. Retesting is also

not required if the processing includes an inactivation step that has

been validated for the viruses concerned.

2.7.

In the case of bone marrow and peripheral blood stem-

cell collection, blood samples must be taken for testing within 30

days prior to donation.

2.8.

In the case of neonatal donors, the biological tests may be

carried out on the donor’s mother to avoid medically unnecessary

procedures upon the infant.

An establishment shall -

(a) ensure that the personnel directly involved in the

procurement, processing, preservation, storage and

distribution of tissues and cells are qualified to

perform such tasks and are provided with timely,

relevant and regularly updated training;

(b) ensure that all donations of human tissues and cells are

subjected to tests in accordance with the requirements

referred to in these regulations and any schedules and

any amendments thereto and that the selection and

acceptance of tissues and cells comply with the

requirements referred to in these regulations and any

schedules and any amendments thereto;

(c) ensure that human tissue and cells and associated

documentation comply with the requirements referred

to in these regulations and any schedules and any

amendments thereto;

(d) verify and record the fact that the packaging of human

tissue and cells received complies with the

requirements referred to in these regulations and any

schedules and any amendments thereto;

(e) discard all tissues and cells that do not comply with

those requirements;

(f)

document the acceptance or rejection of received

tissues or cells;

(g) ensure that human tissues and cells are correctly

identified at all times by assigning an identifying code

to each delivery or batch of tissues or cells in

accordance with regulation 6;

(h) hold tissue and cells in quarantine until such time as

the requirements relating to donor testing and

information have been met in accordance with article

15 of the Act;

(i)

maintain documentation on operational procedures,

guidelines, training and reference manuals and

reporting forms so that they are readily available for

inspection;

(j)

include in their standard operating procedures all

processes that affect quality and safety and shall

ensure that they are carried out under controlled

conditions;

(k) ensure that the equipment used, the working

environment and process design, validation and

control conditions are in compliance with the

requirements referred to in these regulations and any

schedules and any amendments thereto;

(l)

ensure that any modifications to the processes used in

the preparation of tissues and cells shall also meet the

criteria laid down in the preceeding paragraph;

(m) include in their standard operating procedures special

provisions for the handling of tissues and cells to be

discarded, in order to prevent the contamination of

other tissues or cells, the processing environment or

personnel;

(n) ensure that all procedures associated with the storage

of tissues and cells are documented in the standard

operating procedures and that the storage conditions

comply with the requirements referred to in these

regulations and any schedules and any amendments

thereto;

(o) ensure that all storage processes are carried out under

controlled conditions;

(p) establish and apply procedures for the control of

packaging and storage areas, in order to prevent any

situation arising that might adversely affect the

functioning or integrity of tissues and cells;

(q) not to distribute processed tissues and cells until all

the requirements laid down in these regulations and

TISSUES AND CELLS (QUALITY AND SAFETY)

any schedules and any amendments thereto have been

met;

(r) have agreements and procedures in place to ensure

that, in the event of termination of activities for

whatever reason, stored tissues and cells shall be

transferred to other tissue establishment or

establishments licensed by the Authority;

(s) ensure that labelling and documentation and packaging

conform to the requirements set by these regulations

and any schedules and any amendments thereto; and

(t)

ensure that the quality of tissues and cells during

distribution and that the distribution conditions

comply with the requirements set by these regulations

and any schedules and any amendments thereto.

Selection Criteria and Laboratory Tests required for Donors of

Reproductive Cells as referred to in regulation 13(b)

and regulation 14(c)

1. Partner donation for direct use

Donor selection criteria and laboratory testing do not need to be

applied in the case of partner donation of reproductive cells for

direct use.

2. Partner donation (not direct use)

Reproductive cells that are processed and/or stored and

reproductive cells that will result in the cryopreservation of

embryos must meet the following criteria

2.1. the clinician responsible for the donor must determine and

document, based on the patient’s medical history and therapeutic

indications, the justification for the donation and its safety for the

recipient and any child(ren) that might result;

2.2. the following biological tests must be carried out to assess

the risk of cross-contamination

HIV 1 and 2

Anti-HIV-1,2

Hepatitis B

HBsAg

Anti-HBc

Hepatitis C

Anti-HCV-Ab

In case of sperm processed for intrauterine insemination and not

to be stored, if the tissue establishment can demonstrate that the

risk of cross contamination and staff exposure has been addressed

through the use of validated processes, biological testing may not

be required;

2.3. where HIV 1 and 2, hepatitis B or hepatitis C test results

are positive or unavailable, or where the donor is known to be a

source of infection risk, a system of separate storage must be

devised;

2.4. HTLV-I antibody testing must be performed for donors

living in or originating from high-prevalence areas or with sexual

partners originating from those areas or where the donor’s parents

originate from those areas;

2.5. in certain circumstances, additional testing may be

required depending on the donor’s travel and exposure history and

the characteristics of the tissue or cells donated (e.g. Rh D, malaria,

CMV, T. cruzi);

2.6. positive results will not necessarily prevent partner

donation in accordance with national rules.

3. Donations other than by partners

The use of reproductive cells other than for partner donation

must meet the following criteria

3.1. donors must be selected on the basis of their age, health

and medical history, provided on a questionnaire and through a

personal interview performed by a qualified and trained healthcare

professional. This assessment must include relevant factors that

may assist in identifying and screening out persons whose donation

could present a health risk to others, such as the possibility of

transmitting diseases (such as sexually transmitted infections), or

health risks to themselves (e.g. superovulation, sedation or the risks

associated with the egg collection procedure or the psychological

consequences of being a donor);

3.2. the donors must be negative for HIV 1 and 2, HCV, HBV

and syphilis on a serum or plasma sample, tested in accordance

with Schedule III, point 1.1, and sperm donors must additionally be

negative for chlamydia on a urine sample tested by the nucleic acid

amplification technique (NAT);

3.3. HTLV-I antibody testing must be performed for donors

living in or originating from high-prevalence areas or with sexual

partners originating from those areas or where the donor’s parents

originate from those areas;

3.4. in certain circumstances, additional testing may be

required depending on the donor’s history and the characteristics of

the tissue or cells donated (e.g. RhD, malaria, CMV, T. cruzi).

3.5. for autologous donors, SCHEDULE II, point 2.1.1 applies;

3.6. genetic screening for autosomal recessive genes known to

be prevalent, according to international scientific evidence, in the

donor ’s ethnic background and an assessment of the risk of

transmission of inherited conditions known to be present in the

family must be carried out, after consent is obtained. Complete

information must be provided, in accordance with the requirements

in force in Member States. Complete information on the associated

risk and on the measures undertaken for its mitigation must be

communicated and clearly explained to the recipient.

4. General requirements to be met for determining biological

markers

4.1. The tests must be carried out in accordance with Schedule

III, points 2.1 and 2.2.

4.2. (a)

For donations other than by partners, blood samples

must be obtained at the time of each donation.

(b) For donation by partners (not for direct use), blood

samples must be obtained within three months before

the first donation. For further partner donations by the

same donor, further blood samples must be obtained

according to these regulations, but no later than 24

months from the previous sampling.

4.3. Sperm donations other than by partners will be quarantined

for a minimum of 180 days, after which repeat testing is required.

If the blood donation sample is additionally tested by the nucleic

acid amplification technique (NAT) for HIV, HBV and HCV,

testing of a repeat blood sample is not required. Retesting is also

not required if the processing includes an inactivation step that has

been validated for the viruses concerned.

(1)

Tissue establishments shall

(a) establish written agreements with a third party each

time an external activity takes place which influences

the quality and safety of tissues and cells processed in

cooperation with a third party, and in particular in the

following circumstances

(i)

where a tissue establishment entrusts one of the

stages of tissue or cell processing to a third

party;

(ii) where a third party provides goods and services

that affect tissue or cell quality and safety

assurance, including their distribution;

(iii) where a tissue establishment provides services to

a tissue establishment which is not accredited;

(iv) where a tissue establishment distributes tissue or

cells processed by third parties;

(b) evaluate and select third parties on the basis of their

ability to meet the standards laid down in these

regulations and any schedules and any amendments

thereto;

(c) keep a complete list of the agreements referred to in

paragraph (a) which they have established with third

parties; and

(d) provide copies of agreements with third parties at the

request of the competent authority or authorities.

(2) Agreements between tissue establishments and third parties

shall specify the responsibilities of the third parties and detailed

procedures.

Cell and/or Tissue Donation and Procurement Procedures and

Reception at the Tissue Establishment as referred to

in regulation 15

1. Donation and procurement procedures

1.1.

Consent and donor identification

1.1.1. Before the procurement of tissues and cells proceeds, an

authorised person must confirm and record

(a) that consent for the procurement has been obtained in

accordance with regulation 9(a) and (b); and

(b) how and by whom the donor has been reliably

identified.

1.1.2. In the case of living donors, the health professional

responsible for obtaining the health history must ensure that the

donor has

(a) understood the information provided;

(b) had an opportunity to ask questions and been provided

with satisfactory responses;

(c) confirmed that all the information provided is true to

the best of his/her knowledge.

1.2.

Donor evaluation (this section does not apply to partner

donation of reproductive cells or to autologous donors)

1.2.1. An authorised person must collect and record the donor’s

relevant medical and behavioural information according to the

requirements described in section 1.4.

1.2.2. In order to acquire the appropriate information, different

relevant sources must be used, including at least an interview with

the donor, for living donors, and the following when appropriate

(a) the medical records of the donor;

(b) an interview with a person who knew the donor well,

for deceased donors;

(c) an interview with the treating physician;

(d) an interview with the general practitioner;

(e) the autopsy report.

1.2.3. In addition, in the case of a deceased donor, and in the

case of a living donor when justified, a physical examination of the

body must be performed to detect any signs that may be sufficient

in themselves to exclude the donor or which must be assessed in the

light of the donor’s medical and personal history.

1.2.4. The complete donor records must be reviewed and

assessed for suitability and signed by a qualified health

professional.

1.3.

Procurement procedures for tissues and cells

1.3.1. The procurement procedures must be appropriate for the

type of donor and the type of tissue/cells donated.

There must be procedures in place to protect the safety of

the living donor.

1.3.2. The procurement procedures must protect those

properties of the tissue/cells that are required for their ultimate

clinical use, and at the same time minimise the risk of

microbiological contamination during the process, particularly

when tissues and cells cannot subsequently be sterilised.

1.3.3. For deceased donation, the area of access must be

restricted. A local sterile field using sterile drapes must be used.

Staff conducting procurement must be clothed

appropriately for the type of procurement. Usually, this will extend

to being scrubbed, gowned in sterile clothing and wearing sterile

gloves, face shields and protective masks.

1.3.4. In the case of a deceased donor, the place of procurement

must be recorded and the time interval from death to procurement

must be specified so as to ensure that the required biological and/or

physical properties of the tissues/cells are retained.

1.3.5. Once the tissues and cells have been retrieved from a

deceased donor body, it must be reconstructed so that it is as

similar as possible to its original anatomical appearance.

1.3.6. Any adverse event occurring during procurement that has

or may have resulted in harm to a living donor and the outcome of

any investigation to determine the cause must be recorded and

reviewed.

1.3.7. Policies and procedures must be in place to minimise the

risk of tissue or cell contamination by staff who might be infected

with transmissible diseases.

1.3.8. Sterile instruments and devices must be used for tissue

and cell procurement. Instruments or devices must be of good

quality, validated or specifically certified and regularly maintained

for the procurement of tissues and cells.

1.3.9. When reusable instruments must be used, a validated

cleaning and sterilisation procedure for removal of infectious

agents has to be in place.

1.3.10. Wherever possible, only CE marked medical devices

m u s t b e u s e d a n d a l l c o n c e r n e d s t a ff m u s t h a v e r e c e i v e d

appropriate training on the use of such devices.

1.4.

Donor documentation

1.4.1. For each donor, there must be a record containing

(a) the donor identification (first name, family name and

date of birth - if a mother and child are involved in the

donation, both the name and date of birth of the mother

and the name, if known, and date of birth of the child);

(b) age, sex, medical and behavioural history (the

information collected must be sufficient to allow

application of the exclusion criteria, where required);

(c) outcome of body examination, where applicable;

(d) haemodilution formula, where applicable;

(e) the consent/authorisation form, where applicable;

(f)

clinical data, laboratory test results, and the results of

other tests carried out;

(g) if an autopsy was performed, the results must be

included in the record (for tissues and cells that cannot

be stored for extended periods, a preliminary verbal

report of the autopsy must be recorded);

(h) for haematopoietic progenitor cell donors, the donor’s

suitability for the chosen recipient must be

documented.

For unrelated donations, when the organisation

responsible for procurement has limited access to recipient data,

the transplanting organisation must be provided with donor data

relevant for confirming suitability.

1.4.2. The organisation performing the procurement must

produce a procurement report, which is passed on to the tissue

establishment. This report must contain at least

(a) the identification, name and address of the tissue

establishment to receive the cells/tissues;

(b) donor identification data (including how and by whom

the donor was identified);

(c) description and identification of procured tissues and

cells (including samples for testing);

(d) identification of the person who is responsible for the

procurement session, including signing;

(e) date, time (where relevant, start and end) and location

of procurement and procedure (SOP) used, including

any incidents that occurred; where relevant,

environmental conditions at the procurement facility

(description of the physical area where procurement

took place);

(f)

for deceased donors, conditions under which the

cadaver is kept: refrigerated (or not), time of start and

end of refrigeration;

(g) ID/batch numbers of reagents and transport solutions

used.

The report must also contain the date and time of death

where possible.

Where sperm is procured at home, the procurement report

must state this and must contain only

(a) the name and address of the tissue establishment to

receive the cells/tissues;

(b) the donor identification.

The date and time of procurement may be included,

where possible.

1.4.3. All the records must be clear and readable, protected

from unauthorised amendment and retained and readily retrieved in

this condition throughout their specified retention period in

compliance with data protection legislation.

1.4.4. Donor records required for full traceability must be kept

for a minimum of 30 years after clinical use, or the expiry date, in

an appropriate archive acceptable to the Licensing Authority.

1.5.

Packaging

1.5.1. Following procurement, all recovered tissues and cells

must be packaged in a manner which minimises the risk of

contamination and must be stored at temperatures that preserve the

required characteristics and biological function of the cells/tissues.

The packaging must also prevent contamination of those

responsible for packaging and transportation of the tissues and

cells.

1.5.2. The packaged cells/tissues must be shipped in a container

which is suitable for the transport of biological materials and which

maintains the safety and quality of the contained tissue or cells.

1.5.3. Any accompanying tissue or blood samples for testing

must be accurately labelled to ensure identification with the donor,

and must include a record of the time and place the specimen was

taken.

1.6.

Labelling of the procured tissues/cells

At the time of procurement, every package containing

tissues and cells must be labelled. The primary tissue/cell container

must indicate the donation identification or code and the type of

tissues and cells. Where the size of the package permits, the

following information must also be provided

(a) date (and time where possible) of donation;

(b) hazard warnings;

(c) nature of any additives (if used);

(d) in the case of autologous donations, the label must

state ‘for autologous use only’;

(e) in the case of directed donations, the label must

identify the intended recipient.

If any of the information under points (a) to (e) above

cannot be included on the primary package label, it must be

provided on a separate sheet accompanying the primary package.

1.7.

Labelling of the shipping container

When tissues/cells are shipped by an intermediary, every

shipping container must be labelled at least with

(a) TISSUES AND CELLS and HANDLE WITH CARE;

(b) the identification of the establishment from which the

package is being transported (address and phone

number) and a contact person in the event of problems;

(c) the identification of the tissue establishment of

destination (address and phone number) and the person

to be contacted to take delivery of the container;

(d) the date and time of the start of transportation;

(e) specifications concerning conditions of transport

relevant to the quality and safety of the tissues and

cells;

(f)

in the case of all cellular products, the following

indication: DO NOT IRRADIATE;

(g) when a product is known to be positive for a relevant

infectious disease marker, the following indication

BIOLOGICAL HAZARD;

(h) in the case of autologous donors, the following

indication: ‘FOR AUTOLOGOUS USE ONLY’;

(i)

specifications concerning storage conditions (such as

DO NOT FREEZE).

2. Reception of the tissue/cells at the tissue establishment

2.1.

When the retrieved tissues/cells arrive at the tissue

establishment, there must be documented verification that the

consignment, including the transport conditions, packaging,

labelling and associated documentation and samples, meet the

requirements of this Schedule and the specifications of the

receiving establishment.

2.2.

Each establishment must ensure that the tissue and cells

received are quarantined until they, along with the associated

documentation, have been inspected or otherwise verified as

conforming to requirements. The review of relevant donor/

procurement information and thus acceptance of the donation needs

to be carried out by specified/authorised persons.

2.3.

Each tissue establishment must have a documented policy

and specifications against which each consignment of tissues and

cells, including samples, are verified. These must include the

technical requirements and other criteria considered by the tissue

establishment to be essential for the maintenance of acceptable

quality. The tissue establishment must have documented procedures

for the management and segregation of non-conforming

consignments, or those with incomplete test results, to ensure that

there is no risk of contamination of other tissues and cells being

processed, preserved or stored.

2.4.

The data that must be registered at the tissue

establishment (except for donors of reproductive cells intended for

partner donation) include

(a) consent/authorisation; including the purpose(s) for

which the tissues and cells may be used (i.e.

therapeutic or research, or both therapeutic use and

research) and any specific instructions for disposal if

the tissue or cells are not used for the purpose for

which consent was obtained;

(b) all required records relating to the procurement and the

taking of the donor history, as described in the donor

documentation section;

(c) results of physical examination, of laboratory tests and

TISSUES AND CELLS (QUALITY AND SAFETY)

of other tests (such as the autopsy report, if used in

accordance with point 1.2.2.);

(d) for allogeneic donors, a properly documented review

of the complete donor evaluation against the selection

criteria by an authorised and trained person;

(e) in the case of cell cultures intended for autologous use,

documentation of the possibility of medicinal allergies

(such as to antibiotics) of the recipient.

2.5.

In the case of reproductive cells intended for partner

donation, the data to be registered at the tissue establishment

include

(a) consent; including the purpose(s) for which the tissues

and cells may be used (such as reproductive only and/

or for research) and any specific instructions for

disposal if the tissue or cells are not used for the

purpose for which consent was obtained;

(b) donor identification and characteristics: type of donor,

age, sex, presence of risk factors and, in the case of a

deceased donor, the cause of death;

(c) partner identification;

(d) place of procurement;

(e) tissues and cells obtained and relevant characteristics.

An establishment shall ensure that

(a) all tissues and cells procured, processed, stored or

distributed on their territory can be traced from the

donor to the recipient and vice versa. This traceability

shall also apply to all relevant data relating to products

and materials coming into contact with these tissues

and cells;

(b) by means of a donor identification system a unique

code is assigned to each donation and to each of the

products associated with it;

(c) all tissues and cells are identified with a label that

contains the information or references allowing a link

to the information referred to in the schedules to these

regulations and any amendments thereto; and

(d) the data necessary to ensure traceability at all stages is

kept for a minimum of thirty years after clinical use.

Data storage may also be in electronic form.

(1) Tissue establishments shall keep a record of their

activities, including the types and quantities of tissues and, or cells

procured, tested, preserved, processed, stored and distributed, or

otherwise disposed of, and on the origin and destination of the

tissues and cells intended for human applications, in accordance

with the requirements referred to in these regulations and any

schedules and any amendments thereto.

(2) Such establishments shall submit to the Authority an annual

report on these activities which shall be publicly accessible.

An establishment shall

(a) establish and maintain a system to report, investigate,

register and transmit information about serious

adverse events and reactions which may influence the

quality and safety of tissues and cells and which may

be attributed to the procurement, testing, processing,

storage and distribution of tissues and cells, as well as

any serious adverse reaction observed during or after

clinical application which may be linked to the quality

and safety of tissues and cells;

(b) report any relevant information to establishments

engaged in the donation, procurement, testing,

processing, storage and distribution of human tissues

and cells in order to facilitate traceability and ensure

quality and safety control; and

(c) ensure that an accurate, rapid and verifiable procedure

is in place which will enable such establishment to

recall from distribution any product which may be

related to an adverse event or reaction.

An establishment shall, in relation to the procurement of

human tissues or cells

(a) give all prospective donors of tissues or cells, their

relatives or any other person granting consent on

behalf of donors, information in accordance with

guidelines and authorization requirements as

established by the Authority;

(b) obtain from all persons who are willing to donate

tissues or cells, their relatives or any other person

TISSUES AND CELLS (QUALITY AND SAFETY)

granting consent on behalf of donors, information in

accordance with guidelines and authorization

requirements established by the Authority;

(c) put and keep in place procedures for the evaluation of

donors in accordance with the requirements set by

these regulations and schedules and any amendments

thereto;

(d) apply eligibility criteria for all donors of tissues and

cells;

(e) maintain records of the results of donor evaluations

and report to donors any relevant abnormal findings

from the evaluations;

(f)

ensure that

(i)

an examination of the donor, including an

interview, is carried out before any donation of

tissues or cells,

(ii) a qualified health professional is responsible for

giving to and gathering from donors the

information which is necessary to assess their

eligibility to donate, and

(iii) on the basis of that information, a qualified

health professional assesses the eligibility of all

donors to donate;

(g) encourage voluntary and unpaid tissue and cell

donations with a view to ensuring that tissues and cells

are, in so far as possible, provided from such

donations; and

(h) the tissues and cells are procured, packaged and

transported in accordance with the requirements set by

these regulations and any schedules and any

amendments thereto.

(1) An establishment shall ensure that all data, including

genetic information, collated within the scope of the Act and any

regulations made thereunder and to which third parties have access,

have been rendered anonymous so that neither donors nor

recipients remain identifiable.

(2)

For that purpose, the establishment shall ensure that

(a) data security measures are in place, as well as

safeguards against any unauthorised data additions,

deletions or modifications to donor files or deferral

records, and transfer of information;

(b) procedures are in place to resolve data discrepancies;

(c) no unauthorised disclosure of information occurs,

whilst guaranteeing the traceability of donations;

(d) the identity of any recipient is not disclosed to the

donor or his family and vice versa, without prejudice

to any legislation in force on the conditions for

disclosure, notably in the case of gametes donation;

(e) the information which is collected for the purposes of

these regulations is held securely so that it is -

(i) available for the purpose of, tracing donations;

(ii) not disclosed except in accordance with one or

more of the requirements of sub-regulation (3).

(3) The requirements referred to under sub-regulation (2)(e)(ii)

are that the disclosure

(a) shall be in accordance with an order of a court, or as

may otherwise be required by law;

(b) is made to an inspector appointed by the Authority.

(4) The responsible person of the establishment shall ensure

that the results of the donor evaluation and testing procedures are

documented and any major anomalies are reported to the Authority

in accordance with the requirements referred to in Schedule I and

any amendments thereto.

(1) Each tissue establishment shall put in place and update

a quality system based on the principles of good practice.

(2) Such quality system shall include at least the following

documentation

(a) standard operating procedures,

(b) guidelines,

(c) training and reference manuals,

(d) reporting forms,

(e) donor records,

(f)

information on the final destination of tissues or cells.

(3) The documentation referred to in sub-regualtion (2) shall be

available for inspection by an authorised officer.

(4) Tissue establishments shall keep the data necessary to

ensure traceability in accordance with regulation 4.

(1) Procurement of human tissues and cells shall be

carried out by persons who have successfully completed a training

programme specified by a clinical team specialising in the tissues

and cells to be procured or a tissue establishment authorised for

procurement.

(2) The establishment or procurement organisation shall have

written agreements with the staff or clinical teams responsible for

donor selection, unless they are employed by the same organisation

or establishment, specifying the procedures to be followed to

assure compliance with the selection criteria for donors set out in

Schedule II.

(3) The establishment or procurement organisation shall have

written agreements with the staff or clinical teams responsible for

tissue or cell procurement, unless they are employed by the same

establishment or organisation, specifying any type of tissues and,

or cells and, or test samples to be procured and the protocols to be

followed.

(4)

(a) There shall be standard operating procedures (SOPs)

for the verification of

(i) donor identity;

(ii) the details of donor or donor family consent or

authorisation;

(iii) the assessment of the selection criteria for

donors as detailed in regulation 13;

(iv) the assessment of the laboratory tests required

for donors as detailed in regulation 14.

(b) There shall also be SOPs describing the procedures for

procurement, packaging, labelling and transportation

of the tissues and cells to the point of arrival at the

tissue establishment or, in the case of direct

distribution of tissues and cells, to the clinical team

responsible for their application or, in the case of

tissue or cell samples, to the laboratory for testing, in

accordance with regulation 15.

(5) Procurement shall take place in appropriate facilities,

following procedures that minimise bacterial or other

contamination of procured tissues and cells, in accordance with

regulation 15.

(6) Procurement materials and equipment shall be managed in

accordance with the standards and specifications laid down in

section 1.3 of Schedule V, and with due regard to relevant national

and international regulation, standards and guidelines covering the

sterilisation of medicines and medical devices. Qualified, sterile

instruments and procurement devices shall be used for tissue and

cell procurement.

(7) Procurement of tissues and cells from living donors shall

take place in an environment that ensures their health, safety and

privacy.

(8) Where appropriate, the staff and equipment necessary for

body reconstruction of deceased donors shall be provided. Such

reconstruction shall be completed effectively.

(9) The procedures for the procurement of tissues and cells

shall be carried out in accordance with the requirements specified

in regulation 15.

(10) A unique identifying code shall be allocated to the donor

and to the donated tissues and cells, during procurement or at the

tissue establishment, to ensure proper identification of the donor

and the traceability of all donated material. The coded data shall be

entered in a register maintained for the purpose.

(11) Donor documentation shall be maintained in accordance

with section 1.4 of Schedule V.

Tissue and cells establishments shall in respect of donors

adopt the selection criteria set out in these regulations namely

(a) Schedule II for donors of tissues and cells, except

donors of reproductive cells;

(b) Schedule IV for donors of reproductive cells.

It shall be the duty of the establishment to ensure that

(a) donors of tissues and cells, except donors of

reproductive cells, undergo the biological tests set out

in point 1 of Schedule III;

(b) such tests are carried out in compliance with the

general requirements set out in point 2 of Schedule III;

(c) donors of reproductive cells undergo the biological

tests set out in points 1, 2 and 3 of Schedule IV;

(d) such tests are carried out in compliance with the

general requirements set out in point 4 of Schedule IV.

The establishment shall ensure that the tissue and, or cell

donation and procurement procedures and the reception of tissues

and, or cells at the tissue establishment comply with the

requirements set out in Schedule IV.

The Authority may authorise the direct distribution of

specific tissues and cells from where the procurement is carried out

to a health care establishment for immediate transplantation.