HUMAN TISSUES AND CELLS (CODING, PROCESSING, PRESERVATION, STORAGE AND DISTRIBTION) REGULATIONS (storageanddistribtion)

SUBSIDIARY LEGISLATION 483.04

HUMAN TISSUES AND CELLS (CODING,

PROCESSING, PRESERVATION, STORAGE

AND DISTRIBTION) REGULATIONS

1st September, 2007;

1st September, 2008 *

LEGAL NOTICE 337 of 2007, as amended by Legal Notices 304 of 2013,

262 of 2014 and 367 of 2016.

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

Cells (Coding, Processing, Preservation, Storage and Distribution)

Regulations.

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

Directive 2006/86/EC of 24 October 2006 implementing Directive

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

regards traceability requirements, notification of serious adverse

reactions and events and certain technical requirements for the

coding, processing, preservation, storage and distribution of human

tissues and cells.

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

European Parliament and Council Directive 2004/23/EC 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.

(Regulation 4)

Requirements for accreditation, designation, authorisation or licensing

of tissue establishments as referred to in regulation 4

A. ORGANISATION AND MANAGEMENT

1. A responsible person must be appointed having qualifications and

responsibilities as provided in Article 17 of Directive 2004/23/EC.

2. A tissue establishment must have an organisational structure and operational

procedures appropriate to the activities for which accreditation, designation,

authorisation or licensing is sought; there must be an organisational chart which

clearly defines accountability and reporting relationships.

3. Every tissue establishment must have access to a nominated medical

registered practitioner to advise on and oversee the establishment’s medical

activities, such as donor selection, review of clinical outcomes of applied tissues and

cells or interaction as appropriate with clinical users.

4. There must be a documented quality management system applied to the

activities for which accreditation, designation, authorisation or licensing is sought,

in accordance with the standards laid down in Directive 2006/86/EC.

5. It must be ensured that the risks inherent in the use and handling of

biological material are identified and minimised, consistent with maintaining

adequate quality and safety for the intended purpose of the tissues and cells. The

risks include those relating in particular to the procedures, environment, staff health

status specific to the tissue establishment.

6. Agreements between tissue establishments and third parties must comply

with Article 24 of Directive 2004/23/EC. Third party agreements must specify the

terms of the relationship and responsibilities as well as the protocols to be followed

to meet the required performance specification.

7. There must be a documented system in place, supervised by the responsible

person, for ratifying that tissues and, or cells meet appropriate specifications for

safety and quality for release and for their distribution.

8. In the event of termination of activities the agreements concluded and the

procedures adopted in accordance with Article 21(5) of Directive 2004/23/EC shall

include traceability data and material concerning the quality and safety of cells and

tissues.

9. There must be a documented system in place that ensures the identification

of every unit of tissue or cells at all stages of the activities for which accreditation,

designation, authorisation or licensing is sought.

B. PERSONNEL

1. The personnel in tissue establishments must be available in sufficient

number and be qualified for the tasks they perform. The competency of the

personnel must be evaluated at appropriate intervals specified in the quality system.

2. All personnel should have clear, documented and up-to-date job

descriptions. Their tasks, responsibilities and accountability must be clearly

documented and understood.

3. Personnel must be provided with initial and/or basic training, updated

training as required when procedures change or scientific knowledge develops and

adequate opportunities for relevant professional development. The training

programme must ensure and document that each individual

(a) has demonstrated competence in the performance of their designated

tasks;

(b) has an adequate knowledge and understanding of the scientific and/or

technical processes and principles relevant to their designated tasks;

(c) understands the organisational framework, quality system and health

and safety rules of the establishment in which they work, and

(d) is adequately informed of the broader ethical, legal and regulatory

context of their work.

C. EQUIPMENT AND MATERIALS

1. All equipment and material must be designed and maintained to suit its

intended purpose and must minimise any hazard to recipients and/or staff.

2. All critical equipment and technical devices must be identified and

validated, regularly inspected and preventively maintained in accordance with the

manufacturers’ instructions. Where equipment or materials affect critical processing

or storage parameters (e.g. temperature, pressure, particle counts, microbial

contamination levels), they must be identified and must be the subject of appropriate

monitoring, alerts, alarms and corrective action, as required, to detect malfunctions

and defects and to ensure that the critical parameters are maintained within

acceptable limits at all times. All equipment with a critical measuring function must

be calibrated against a traceable standard if available.

3. New and repaired equipment must be tested when installed and must be

validated before use. Test results must be documented.

4. Maintenance, servicing, cleaning, disinfection and sanitation of all critical

equipment must be performed regularly and recorded accordingly.

5. Procedures for the operation of each piece of critical equipment, detailing

the action to be taken in the event of malfunctions or failure, must be available.

6. The procedures for the activities for which accreditation, designation,

authorisation, licensing is sought, must detail the specifications for all critical

materials and reagents. In particular, specifications for additives (e.g. solutions) and

packaging materials must be defined. Critical reagents and materials must meet

documented requirements and specifications and when applicable the requirements

of Council Directive 93/42/EEC of 14 June 1993 concerning medical devices and

Directive 98/79/EC of the European Parliament and of the Council of 27 October

1998 on in vitro diagnostic medical devices.

D. FACILITIES / PREMISES

1. A tissue establishment must have suitable facilities to carry out the activities

for which accreditation, designation, authorisation or licensing is sought, in

accordance with the standards laid down herein.

2. When these activities include processing of tissues and cells while exposed

to the environment, this must take place in an environment with specified air quality

and cleanliness in order to minimise the risk of contamination, including cross-

contamination between donations. The effectiveness of these measures must be

validated and monitored.

3. Unless otherwise specified in point 4, where tissues or cells are exposed to

the environment during processing, without a subsequent microbial inactivation

process, an air quality with particle counts and microbial colony counts equivalent to

those of Grade A as defined in the current European Guide to Good Manufacturing

Practice (GMP), Annex 1 and Directive 2003/94/EC is required with a background

environment appropriate for the processing of the tissue/cell concerned but at least

equivalent to GMP Grade D in terms of particles and microbial counts.

4. A less stringent environment than specified in point 3 may be acceptable

where

(a) a validated microbial inactivation or validated terminal sterilisation

process is applied; or

(b) where it is demonstrated that exposure in a Grade A environment has a

detrimental effect on the required properties of the tissue or cell

concerned; or

(c) where it is demonstrated that the mode and route of application of the

tissue or cell to the recipient implies a significantly lower risk of

transmitting bacterial or fungal infection to the recipient than with cell

and tissue transplantation; or

(d) where it is not technically possible to carry out the required process in a

Grade A environment (for example, due to requirements for specific

equipment in the processing area that is not fully compatible with Grade

A).

5. In point 4(a), (b), (c) and (d), an environment must be specified. It must be

demonstrated and documented that the chosen environment achieves the quality and

safety required, at least taking into account the intended purpose, mode of

application and immune status of the recipient. Appropriate garments and equipment

for personal protection and hygiene must be provided in each relevant department of

the tissue establishment along with written hygiene and gowning instructions.

6. When the activities for which accreditation, designation, authorisation or

licensing is sought involve storage of tissues and cells, the storage conditions

necessary to maintain the required tissue and cell properties, including relevant

parameters such as temperature, humidity or air quality must be defined.

7. Critical parameters (e.g. temperature, humidity, air quality) must be

controlled, monitored, and recorded to demonstrate compliance with the specified

storage conditions.

8. Storage facilities must be provided that clearly separate and distinguish

tissues and cells prior to release/in quarantine from those that are released and from

those that are rejected, in order to prevent mix-up and cross-contamination between

them. Physically separate areas or storage devices or secured segregation within the

device must be allocated in both quarantine and released storage locations for

holding certain tissue and cells collected in compliance with special criteria.

9. The tissue establishment must have written policies and procedures for

controlled access, cleaning and maintenance, waste disposal and for the re-provision

of services in an emergency situation.

E. DOCUMENTATION AND RECORDS

1. There must be a system in place that results in clearly defined and effective

documentation, correct records and registers and authorised Standard Operating

Procedures (SOPs), for the activities for which accreditation, designation,

authorisation or licensing is sought. Documents must be regularly reviewed and

must conform to the standards laid down herein. The system must ensure that work

performed is standardised, and that all steps are traceable; i.e. coding, donor

eligibility, procurement, processing, preservation, storage, transport, distribution or

disposal, including aspects relating to quality control and quality assurance.

2. For every critical activity, the materials, equipment and personnel involved

must be identified and documented.

3. In the tissue establishments all changes to documents must be reviewed,

dated, approved, documented and implemented promptly by authorised personnel.

4. A document control procedure must be established to provide for the history

of document reviews and changes and to ensure that only current versions of

documents are in use.

5. Records must be shown to be reliable and a true representation of the

results.

6. Records must be legible and indelible and may be handwritten or transferred

to another validated system, such as a computer or microfilm.

7. Without prejudice to Article 9(2), all records, including raw data, which are

critical to the safety and quality of the tissues and cells shall be kept so as to ensure

access to these data for at least ten years after expiry date, clinical use or disposal.

8. Records must meet the confidentiality requirements laid down in Article 14

of Directive 2004/23/EC. Access to registers and data must be restricted to persons

authorised by the responsible person, and to the competent authority for the purpose

of inspection and control measures.

F. QUALITY REVIEW

1. An audit system must be in place for the activities for which accreditation,

designation, authorisation or licensing is sought. Trained and competent persons

must conduct the audit in an independent way, at least every two years, in order to

verify compliance with the approved protocols and the regulatory requirements.

Findings and corrective actions must be documented.

2. Deviations from the required standards of quality and safety must lead to

documented investigations, which include a decision on possible corrective and

preventive actions. The fate of non-conforming tissues and cells must be decided in

accordance with written procedures supervised by the responsible person and

recorded. All affected tissues and cells must be identified and accounted for.

3. Corrective actions must be documented, initiated and completed in a timely

and effective manner. Preventive and corrective actions should be assessed for

effectiveness after implementation.

4. The tissue establishment should have processes in place for review of the

performance of the quality management system to ensure continuous and systematic

improvement.

(1) These regulations shall apply to the coding, processing,

preservation, storage and distribution of

(a) human tissues and

cells

intended

for

human

applications; and

(b) manufactured products derived from human tissues

and cells intended for human applications, where those

products are not covered by other directives.

(2) The provisions of regulations 6 to 9 of these regulations,

concerning traceability and the reporting of serious adverse

reactions and events shall also apply to the donation, procurement

and testing of human tissues and cells.

(3)

These regulations shall not apply to

(a) tissues and cells used as an autologous graft within the

same surgical procedure;

(b) blood and blood components as defined by Directive

2002/98/EC of the European Parliament and of the

Council of 27 January 2003 setting standards of

quality and safety for the collection, testing,

*see regulation 1(3) of these Regulations, as originally promulgated.

processing, storage and distribution of human blood

and blood components and amending Directive 2001/

83/EC;

(c) organs or parts of organs if it is their function to be

used for the same purpose as the entire organ in the

human body.

Amended by

L.N. 367 of 2016.

(Regulation 5)

Requirements for the authorisation of tissue and cell preparation processes

at the tissue establishments as referred to in regulation 5

The competent authority shall authorise each tissue and cell preparation process

after evaluation of the donor selection criteria and procurement procedures, the

protocols for each step of the process, the quality management criteria, and the final

quantitative and qualitative criteria for cells and tissues. This evaluation must

comply at least with the requirements set out in this Schedule.

A. RECEPTION AT THE TISSUE ESTABLISHMENT

Upon reception of procured tissues and cells at the tissue establishment, the

tissues and cells must comply with the requirements defined in Directive 2006/17/

EC.

B. PROCESSING

When the activities for which the accreditation, designation, authorisation or

licensing is sought include processing of tissues and cells, the tissue establishment

procedures must comply with the following criteria

1. The critical processing procedures must be validated and must not render the

tissues or cells clinically ineffective or harmful to the recipient. This validation may

be based on studies performed by the establishment itself, or on data from published

studies or, for well established processing procedures, by retrospective evaluation of

the clinical results for tissues supplied by the establishment.

2. It has to be demonstrated that the validated process can be carried out

consistently and effectively in the tissue establishment environment by the staff.

3. The procedures must be documented in SOPs which must conform to the

validated method and to the standards laid down herein, accordingly with Schedule I

(E), points 1 to 4.

4. It must be ensured that all processes are conducted in accordance with the

approved SOPs.

5. Where a microbial inactivation procedure is applied to the tissue or cells, it

must be specified, documented, and validated.

6. Before implementing any significant change in processing, the modified

process must be validated and documented.

7. The processing procedures must undergo regular critical evaluation to

ensure that they continue to achieve the intended results.

8. Procedures for discarding tissue and cells must prevent the contamination of

other donations and products, the processing environment or personnel. These

procedures must comply with national regulations.

C. STORAGE AND RELEASE OF PRODUCTS

When the activities for which the accreditation, designation, authorisation or

licensing is sought include storage and release of tissues and cells, the authorised

tissue establishment procedures must comply with the following criteria

1. Maximum storage time must be specified for each type of storage condition.

The selected period must reflect among others possible deterioration of the required

tissue and cell properties.

2. There must be a system of inventory hold for tissues and/or cells to ensure

that they cannot be released until all requirements laid down herein have been

satisfied. There must be a standard operating procedure that details the

circumstances, responsibilities and procedures for the release of tissues and cells for

distribution.

3. A system for identification of tissues and cells throughout any phase of

processing in the tissue establishment must clearly distinguish released from non-

released (quarantined) and discarded products.

4. Records must demonstrate that before tissues and cells are released all

appropriate specifications are met, in particular all current declaration forms,

relevant medical records, processing records and test results have been verified

according to a written procedure by a person authorised for this task by the

responsible person as specified in Article 17 of Directive 2004/23/EC. If a computer

is used to release results from the laboratory, an audit trail should indicate who was

responsible for their release.

5. A documented risk assessment approved by the responsible person as

defined in Article 17 of Directive 2004/23/EC must be undertaken to determine the

fate of all stored tissues and cells following the introduction of any new donor

selection or testing criterion or any significantly modified processing step that

enhances safety or quality.

D. DISTRIBUTION AND RECALL

When the activities for which the accreditation, designation, authorisation or

licensing is sought include distribution of tissues and cells, the authorised tissue

establishment procedures must comply with the following criteria

1. Critical transport conditions, such as temperature and time limit, must be

defined to maintain the required tissue and cell properties.

2. The container/package must be secure and ensure that the tissue and cells

are maintained in the specified conditions. All containers and packages need to be

validated as fit for purpose.

3. Where distribution is carried out by a contracted third party, a documented

agreement must be in place to ensure that the required conditions are maintained.

4. There must be personnel authorised within the tissue establishment to assess

the need for recall and to initiate and coordinate the necessary actions.

5. An effective recall procedure must be in place, including a description of the

responsibilities and actions to be taken. This must include notification to the

competent authority.

6. Actions must be taken within pre-defined periods of time and must include

tracing all relevant tissues and cells and, where applicable, must include trace-back.

The purpose of the investigation is to identify any donor who might have contributed

to causing the reaction in the recipient and to retri/eve available tissues and cells

from that donor, as well as to notify consignees and recipients of tissues and cells

procured from the same donor in the event that they might have been put at risk.

7. Procedures must be in place for the handling of requests for tissues and

cells. The rules for allocation of tissues and cells to certain patients or health care

institutions must be documented and made available to these parties upon request.

8. A documented system must be in place for the handling of returned products

including criteria for their acceptance into the inventory, if applicable.

E. FINAL LABELLING FOR DISTRIBUTION

1. The primary tissue/cell container must provide

(a) type of tissues and cells, identification number or code of the tissue/

cells, and lot or batch number where applicable;

(b) identification of the tissue establishment;

(c) expiry date;

(d) in the case of autologous donation, this has to be specified (for

autologous use only) and the donor/recipient has to be identified;

(e) in the case of directed donations - the label must identify the intended

recipient;

(f)

when tissues and cells are known to be positive for a relevant infectious

disease marker, it must be marked as: BIOLOGICAL HAZARD;

(g) Single European Code as applicable to the tissues and cells being

distributed for human application or the donation identification

sequence as applicable to the tissues and cells released for circulation,

other than distributed for human application.

If any of the information under points (d), (e) and (g) above cannot be included on

the primary container label, it must be provided on a separate sheet accompanying

the primary container. This sheet must be packaged with the primary container in a

manner that ensures that they remain together.

2. The following information must be provided either on the label or in

accompanying documentation

(a) description (definition) and, if relevant, dimensions of the tissue or cell

product;

(b) morphology and functional data where relevant;

(c) date of distribution of the tissue/cells;

(d) biological determinations carried out on the donor and results;

(e) storage recommendations;

(f)

instructions for opening the container, package, and any required

manipulation/reconstitution;

(g) expiry dates after opening/manipulation;

(h) instructions for reporting serious adverse reactions and/or events as set

out in regulations 6 and 7;

(i)

presence of potential harmful residues (e.g. antibiotics, ethylene oxide

etc);

(j)

for imported tissues and cells, the country of procurement and the

exporting country (if different from the procurement country).

F. EXTERNAL LABELLING OF THE SHIPPING CONTAINER

For transport, the primary container must be placed in a shipping container that

must be labelled with at least the following information

(a) identification of the originating tissue establishment, including an

address and phone number;

(b) identification of the organisation responsible for human application of

destination, including address and phone number;

(c) a statement that the package contains human tissue/cells and HANDLE

WITH CARE;

(d) where living cells are required for the function of the graft, such as stem

cells gametes and embryos, the following must be added: “DO NOT

IRRADIATE”;

(e) recommended transport conditions (e.g. keep cool, in upright position,

etc.);

(f)

safety instructions/method of cooling (when applicable).

For the purposes of these regulations

"the Authority" means the Licensing Authority;

"critical" means potentially having an effect on the quality and,

or safety of, or having contact with, the cells and tissues;

"donation identification sequence" means the first part of the

Single European Code consisting of the EU tissue establishment

code and the unique donation number;

"EU Coding Platform" means the IT platform hosted by the

C o m m i s s i o n w h i c h c o n t a i n s t h e E U Ti s s u e E s t a b l i s h m e n t

Compendium and the EU Tissue and Cell Product Compendium;

"EU Tissue and Cell Product Compendium" means the register of

all types of tissues and cells circulating in the Union and the

respective product codes under the three permitted coding systems

(EUTC, ISBT128 and Eurocode);

"EU tissue establishment code" means the unique identifier for

accredited, designated, authorised, or licensed tissue

establishments in the Union. The tissue establishment code consists

of an ISO country code and the tissue establishment number set out

in the EU Tissue Establishment Compendium, as further specified

in Schedule VII to these regulations;

"EU Tissue Establishment Compendium" means the register of

all tissue establishments which are authorised, licensed, designated

or accredited by the Member States’ competent authority or

authorities and which contains the information about these tissue

establishments as set out in Schedule VIII;

"EUTC" means the product coding system for tissues and cells

developed by the Union consisting of a register of all types of

tissues and cells circulating in the Union and their corresponding

product codes;

"expiry date" means the date by which the tissues and cells can

be applied, as further defined in Schedule VII;

"organisations responsible for human application" means a

health care establishment or a unit of a hospital or another body

which carries out human application of human tissues and cells;

"partner donation" means the donation of reproductive cells

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

physical relationship;

"pooling" means the physical contact or mixing in a single

container, of tissues or cells from more than one procurement from

the same donor, or from two or more donors;

"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;

"product code" means the identifier for the specific type of tissue

and cell in question. The product code consists of the product

coding system identifier indicating the coding system used by the

tissue establishment ("E" for the EUTC, "A" for ISBT128, "B" for

Eurocode) and the tissues and cells product number foreseen in the

respective coding system for the product type, as further defined in

Schedule VII;

"product identification sequence" means the second part of the

Single European Code consisting of the product code, the split

number and the expiry date;

"qualification" has the same meaning as "validation";

"quality management" means the coordinated activities to direct

and control an organisation with regard to quality;

"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;

"released for circulation" means distribution for human

app licati on or t ransfer to another o perat or, e.g. for further

processing with or without return;

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

used for the purpose of assisted reproduction;

"Single European Code" or "SEC" means the unique identifier

applied to tissues and cells distributed in the Union. The Single

European Code consists of a donation identification sequence and a

product identification sequence, as further specified in Schedule

VII;

"split number" means the number which distinguishes and

uniquely identifies tissues and cells having the same unique

donation number and the same product code and originating from

the same tissue establishment, as further defined in Schedule VII;

" St a n d a r d O p e r a t i n g P r o c e d u r e s " ( S O P s ) m e a n s w r i t t e n

instructions describing the steps in a specific process, including the

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

"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 the recipients

a t t h e m e d ic a l f a c i li t ie s ap pl yin g t h e ti s s u e o r c e l ls t o t h e

recipients; 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;

"unique donation number" means the unique number attributed to

a specific donation of tissues and cells in line with the system in

place in each Member State for allocating such numbers, as further

specified in Schedule VII;

"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, 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;

"within the same centre" means that all steps from procurement

to human application are carried out under the same responsible

person, quality management system and traceability system, within

a healthcare centre comprising at least an accredited, designated,

authorised, or licensed tissue establishment and an organisation

responsible for human application at the same location.

Substituted by

L.N. 367 of 2016.

(Regulation 6(3))

NOTIFICATION OF SERIOUS ADVERSE REACTIONS

Part A

Rapid notification for suspected serious adverse reactions

Tissue establishment

EU tissue establishment code (if applicable)

Report identification

Reporting date (year/month/day)

Individual affected (recipient or donor)

Date and place of procurement or human application (year/month/day)

Unique donation identification number

Date of suspected serious adverse reaction (year/month/day)

Type of tissues and cells involved in the suspected serious adverse reaction

Single European Code of tissues or cells involved in the suspected serious

adverse reaction (if applicable)

Type of suspected serious adverse reaction(s)

PART B

Conclusions of Serious Adverse Reactions Investigation

Tissue establishment

EU tissue establishment code (if applicable)

Report identification

Confirmation date (year/month/day)

Date of serious adverse reaction (year/month/day)

Unique donation identification number

Confirmation of serious adverse reaction (Yes/No)

Single European Code of tissues or cells involved in the confirmed serious

adverse reaction (if applicable)

Change of type of serious adverse reaction (Yes/No) If YES, specify

Clinical outcome (if known)

-

Complete recovery

-

Minor sequelae

-

Serious sequelae

-

Death

Outcome of the investigation and final conclusions

Recommendations for preventive and corrective actions

A tissue establishment shall, for the purposes of its

accreditation, designation, authorisation or licensing, comply with

the requirements set out in Schedule I.

Amended by

L.N. 262 of 2014.

(Regulation 7(5))

Substituted by

L.N. 367 of 2016.

Part A - NOTIFICATION OF SERIOUS ADVERSE EVENTS

Rapid notification for suspected serious adverse events

Tissue establishment

EU tissue establishment code (if applicable)

Report identification

Reporting date (year/month/day)

Date of serious adverse event (year/month/day)

Serious adverse event, Specification

w h i c h m a y a f f e c t Tissues and Equipment

Human error

Other

quality and safety of cells defect

failure

(specify)

tissues and cells due to

a deviation in

Procurement

Testing

Transport

Processing

Storage

Distribution

Materials

Others (specify)

PART B

Conclusions of Serious Adverse Events investigation

Tissue establishment

EU tissue establishment code (if applicable)

Report identification

Confirmation date (year/month/day)

Date of serious adverse event (year/month/day)

Root cause analysis (details)

Corrective measures taken (details)

Preparation processes at the tissue establishments shall, for

the purposes of its accreditation, designation, authorisation or

licensing, comply with the requirements set out in Schedule II.

(Regulation 8(2))

Part A - ANNUAL NOTIFICATION FORMAT

Annual Notification Format for Serious Adverse Reactions

Reporting country

Reporting date 1 January - 31 December (year)

Number of serious adverse reaction(s) per type of tissue and cell (or products in

contact with the tissues and cells)

Type of tissue/cell (or

Total number of tissues/

Number of serious adverse

product in contact with

cells of this type

reaction(s)

the tissues and cells)

distributed (if available)

.....

Total

Total number of tissues and cells distributed (including type of tissue and cell for

which no serious adverse reactions were reported)

Number of recipients affected (total number of recipients)

Nature of the serious adverse reactions To t a l n u m b e r o f s e r i o u s a d v e r s e

reported

reaction(s)

Transmitted bacterial infection

T r a n s m i t t e d v i r a l HBV

infection

HCV

HIV-1/2

Other (Specify)

Transmit ted

Malaria

parasitical infection

Other (Specify)

Transmitted malignant diseases

Other disease transmissions

Other serious reactions (Specify)

Part B

ANNUAL NOTIFICATION FORMAT FOR SERIOUS ADVERSE EVENTS

Notification for suspected serious adverse events

Reporting country

Reporting date 1 January - 31 December (year)

Total number of tissues and cells processed

Total number of serious

Specification

adverse events, which may Tissues and Equipment

Human

Other

have affected quality and

cells defect

failure

error

(specify)

safety of tissues due to a

(specify)

(specify)

(specify)

deviation in

Procurement

Testing

Transport

Processing

Storage

Distribution

Materials

Others (specify)

(1)

The Authority shall ensure that

(a) procurement organisations have procedures in place to

retain the records of tissues and cells procured and to

notify tissue establishments without delay of any

serious adverse reactions in the living donor which

may influence the quality and safety of tissues and

cells;

(b) organisations responsible for human application of

tissues and cells have procedures in place to retain the

records of tissues and cells applied and to notify tissue

establishments without delay of any serious adverse

reactions observed during and after clinical

application which may be linked to the quality and

safety of tissues and cells;

(c) tissue establishments that distribute tissue and cells for

human application provide information to the

organisation responsible for human application of

tissues and cells about how that organisation should

report serious adverse reactions as referred to in

paragraph (b).

(2) The Authority shall ensure that tissue establishments have

procedures in place to communicate to it without delay

(a) all relevant available information about suspected

serious adverse reactions as referred to in sub-

regulation (1)(a) and (b); and

(b) the conclusion of the investigation to analyse the cause

and the ensuing outcome.

(3) It shall be the duty of the responsible person of a tissue

establishment to notify the Authority of the -

(a) information included in the notification set out in Part

A of Schedule III;

(b) actions taken with respect to other implicated tissues

and cells that have been distributed for human

applications;

(c) conclusion of the investigation, supplying at least the

information set out in Part B of Schedule III.

Substituted by

L.N. 367 of 2016.

(Regulation 9(2))

Minimum data to be kept in accordance with regulation 10(2)

A. BY TISSUE ESTABLISHMENTS

(1)

Donor identification

(2)

Donation identification that will include at least

-

Identification of the procurement organisation (including contact

details) or the tissue establishment

-

Unique donation number

-

Date of procurement

-

Place of procurement

-

Type of donation (e.g. single v multi-tissue; autologous v allogenic;

living v deceased)

(3)

Product identification that will include at least

-

Identification of the tissue establishment

-

Type of tissue and cell/product (basic nomenclature)

-

Pool number (in case of pooling)

-

Split number (if applicable)

-

Expiry date (if applicable)

Tissue/cell status (i.e. quarantined, suitable for use, etc.)

Description and origin of the products, processing steps applied,

materials and additives coming into contact with tissues and cells and

having an effect on their quality and/or safety.

Identification of the facility issuing the final label

(4)

Single European Code (if applicable)

(5)

Human application identification that will include at least

Date of distribution/disposal

Identification of the clinician or end-user/facility

B. BY ORGANISATIONS RESPONSIBLE FOR HUMAN APPLICATION

(1)

Identification of the supplier tissue establishment

(2)

Identification of the clinician or end-user/facility

(3)

Type of tissues and cells

(4)

Product identification

(5)

Identification of the recipient

(6)

Date of application

(7)

Single European Code (if applicable)

(1) All persons or establishments using human tissues and

cells regulated by these regulations shall 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 shall have procedures in place for this

purpose.

(2)

It shall be the duty of -

(a) procurement organisations and tissue establishments to

have procedures in place to retain the records and to

notify tissue establishments without delay of any

serious adverse events that occur during procurement

which may influence the quality and, or safety of

human tissues and cells;

(b) organisations responsible for human application of

tissues and cells to have procedures in place to notify

tissue establishments without delay of any serious

adverse events that may influence the quality and

safety of the tissues and cells;

(c) tissue establishments to provide to the organisation

responsible for human application information about

how that organisation should report serious adverse

events to them that may influence the quality and

safety of the tissues and cells.

(3) In the case of assisted reproduction, any type of gamete or

embryo misidentification or mix-up shall be considered to be a

serious adverse event. All persons or procurement organisations or

organisations responsible for human application performing

assisted reproduction shall report such events to the supplying

tissue establishments for investigation and notification to the

Authority.

(4)

It shall be the duty of tissue establishments to -

(a) have procedures in place to communicate to the

Authority without delay all relevant available

information about suspected serious adverse events as

referred to in sub-regulation (2)(a) and (b);

(b) have procedures in place to communicate to the

Authority without delay the conclusion of the

investigation to analyse the cause and the ensuing

outcome.

(5)

(a) It shall be the duty of the responsible person of a tissue

and cell establishment to notify the Authority of the

information included in the notification set out in Part

A of Schedule IV.

(b) It shall be the duty of tissue establishments to

(i)

evaluate serious adverse events to identify

preventable causes within the process;

(ii) notify the Authority of the conclusion of the

investigation, supplying at least the information

set out in Part B of Schedule IV.

Substituted by

L.N. 367 of 2016.

(Regulation 10(2))

THE STRUCTURE OF THE SINGLE EUROPEAN CODE

DONATION IDENTIFICATION

PRODUCT IDENTIFICATION SEQUENCE

SEQUENCE

EU TISSUE

UNIQUE

PRODUCT CODE

ESTABLISHMENT

DONATION

SPLIT

EXPIRY

CODE

NUMBER

NUMBER

DATE

Tissue

Product

Product

(YYYYM

country establishment

Coding

number

MDD)

number

System

identifier

6 alpha-

13 alpha-

1 alphabetic

7 alpha-

3 alpha-

8 numeric

numeric

numeric

character

numeric

numeric

characters

characters

characters

characters

characters

(1) The Licensing Authority shall organise inspections and

carry out control measures as appropriate whenever there is any

serious adverse reaction or serious adverse event. In addition, such

an inspection shall be organised and control measures shall be

carried out at the duly justified request of the competent authority

or authorities in another Member State in any such case.

(2) The Licensing Authority shall, upon the request of another

Member State or the Commission, provide information on the

results of inspections and control measures carried out in relation to

the requirements of these regulations.

Added by

L.N. 367 of 2016.

(Regulation 13(2))

Data to be recorded in the EU Tissue Establishment Compendium

Tissue establishment information

1. Name of the tissue establishment

2. National or international code of tissue establishment

3. Name of the organisation in which the tissue establishment is located (if

applicable)

4. Address of the tissue establishment

5. Publishable contact details: functional e-mail address, phone and fax

Details on the authorisation, accreditation, designation, or license of the

tissue establishment

1. Name of the authorising, accrediting, designating or licensing

competent authority or authorities

2. Name of the national competent authority or authorities responsible for

maintenance of the EU Tissue Establishment Compendium

3. Name of the authorisation, accreditation, designation or licence holder

(if applicable)

4. Tissues and cells for which the authorisation, accreditation, designation

or license was granted

5. Activities actually carried out for which the authorisation, accreditation,

designation or licence was granted

6. Status of the authorisation, accreditation, designation or license

(authorised, suspended, revoked, in part or in full, voluntary cessation

of activities)

Details of any conditions and exemptions added to the authorisation (if

applicable).

(1) The Authority shall submit to the Commission an

annual report, by the 30th June of the following year, on the

notification of serious adverse reactions and events received by it.

The Commission shall submit to the competent authorities of

Member States a summary of the reports received. The Authority

shall make this report available to tissue establishments.

(2) Data transmission shall comply with the data exchange

format specifications as set out in Schedule V, Parts A and B, and

shall provide all the information necessary to identify the sender

and maintain its reference data.

(1) The Authority shall ensure that tissues and cells are

traceable in particular through documentation and the use of the

Single European Code from procurement to human application or

disposal and vice versa. Tissues and cells used for advanced

therapy medicinal products shall be traceable under these

regulations at least until transferred to the ATMP manufacturer.

(2) The Authority shall ensure that tissue establishments and

organisations responsible for human application shall retain the

data set out in Schedule VI for at least thirty years, using an

appropriate and readable storage medium.

(3) Where tissues and cells retrieved from a deceased donor by

procurement teams operating for two or more tissue establishments,

the Authority shall ensure an appropriate traceability system across

the procurements..

(1) Without prejudice to sub-regulation (2), a Single

European Code shall be applied to all tissues and cells distributed

for human application. For the other situations where tissues and

cells are released for circulation, as a minimum the donation

identification sequence shall be applied at least in the

accompanying documentation.

(2)

The provisions of sub-regulation (1) shall not apply to

(a) reproductive cells from partner donation;

(b) tissues and cells distributed directly for immediate

transplantation to the recipient, as provided for under

the Tissues and Cells (Quality and Safety)

Regulations;

(c) tissues and cells imported into the Union in case of

emergency authorised directly by the competent

authority or authorities, as referred to in the Human

Blood and Transplants Act;

(d) tissues and cells other than reproductive cells for

partner donation, when these tissues and cells remain

within the same centre; and

(e) tissues and cells that are imported into the Union,

when these tissues and cells remain within the same

centre from importation to application, provided that

the centre comprises a tissue establishment authorised,

designated, accredited, or licensed to carry out

importing activities.

The Single European Code referred to in the regulation 11

shall, apart from the requirements provided for under Schedule VII,

(a) in eye-readable format;

(b) preceded by the acronym "SEC"; and

(c) printed with the Donation Identification Sequence and

Product Identification Sequence separated by a single

space or as two successive lines.

(1) The Authority shall ensure that all tissue

establishments, including importing tissue establishments (as

defined in Directive 2015/565/EU, as amended) -

(a) allocate a Single European Code to all tissues and cells

requiring application of this code at the latest before

their distribution for human application;

(b) allocate a donation identification sequence after

procuring the tissues and cells, or when receiving them

from a procurement organisation, or when importing

tissues and cells from a third country supplier. The

donation identification sequence shall include

(i)

their EU tissue establishment code as assigned in

the EU Tissue Establishment Compendium;

(ii) a unique donation number allocated by the tissue

establishment, unless such number is allocated

HUMAN TISSUES AND CELLS (CODING, PROCESSING,

PRESERVATION, STORAGE AND DISTRIBUTION)

centrally at national level or is a globally unique

number as used by the ISBT128 coding system.

Where allowed, in case of pooling of tissues and

cells, a new donation identification number shall

be allocated to the final product;

(c) do not alter the donation identification sequence once

it is allocated to tissues and cells released for

circulation, unless it is necessary to correct an

encoding error; any correction requires proper

documentation;

(d) use one of the permitted product coding systems and

the corresponding tissue and cell product numbers

included in the EU Tissue and Cell Product

Compendium at the latest before their distribution for

human application;

(e) use an appropriate split number and expiry date. For

tissues and cells for which no expiry date is defined,

the expiry date shall be 00000000 at the latest before

their distribution for human application;

(f)

apply the Single European Code on the label of the

product concerned in an indelible and permanent

manner and mention that code in the relevant

accompanying documentation at the latest before its

distribution for human application. The tissue

establishment may entrust this task to a third party or

third parties, provided the tissue establishment ensures

compliance with Directive 2015/565/EU, as amended,

in particular in terms of uniqueness of the code. Where

the label size precludes the application of the Single

European Code on the label, the code shall be

unambiguously linked to tissues and cells packaged

with such a label through the accompanying

documentation;

(g) notify the competent authority when

(i)

information contained in the EU Tissue

Establishment Compendium requires an update

or correction;

(ii) the EU Tissue and Cell Product Compendium

requires an update;

(iii) the tissue establishment observes a situation of

significant

non-compliance

with

the

requirements relating to the Single European

Code concerning tissues and cells received from

other EU tissue establishments;

(h) take the necessary measures in case of incorrect

application of the Single European Code on the label.

(2)

The Authority shall also

(a) ensure the allocation of a unique tissue establishment

number to all tissue establishments authorised,

accredited, designated or licensed in Malta. If a tissue

establishment has different physical locations, but has

one system for allocating unique donation numbers, it

may be deemed to be one and the same tissue

establishment. If a tissue establishment uses two or

more systems to allocate unique donation numbers,

such an entity shall be allocated separate tissue

establishment numbers corresponding to the number of

allocation systems used;

(b) decide which system or systems shall be used for the

allocation of unique donation numbers in Malta.

Permitted systems of allocation include national

systems establishing centralised allocation of the

nationally unique donation number or systems

requiring each tissue establishment to allocate unique

donation numbers or international systems that

allocate globally unique donation numbers that are

compatible with the Single European Code;

(c) monitor and enforce the full implementation of the

Single European Code in Malta;

(d) ensure the validation of the data on the tissue

establishments contained in the EU Tissue

Establishment Compendium in Malta and update the

Compendium, in not later than ten working days for

any changes substantially affecting the authorisation,

accreditation, designation or licence of the tissue

establishments concerned, in particular for the

following situations

(i)

when a new tissue establishment is authorised,

designated, accredited, or licensed;

(ii) when tissue establishment information changes

or is not correctly recorded in the EU Tissue

Establishment Compendium;

(iii) when

the

accreditation,

designation,

authorisation or licence details of a tissue

establishment, as listed in Schedule VIII,

change, including

(A) accreditation, desi-gnation, authorisation

or licence for a new tissue or cell type;

(B) accreditation, desi-gnation, authorisation

or licence for a new prescribed activity;

(C) details of any conditions and, or

exemptions added to an authorisation;

(D) suspension, in part or in full, of a specific

accreditation, designation, authorisation or

licence for a particular activity or tissue or

cell type;

(E) revocation, in part or in full, of an

accreditation, designation, authorisation or

licence for a tissue establishment; and

(F) situations when a tissue establishment

voluntarily ceases, in part or in full, the

activity or activities for which it is

authorised, accredited, designated or

licensed

Provided that when a tissue establishment is

authorised by two or more competent authorities for

different types of tissues and cells or different

activities, each competent authority shall update the

information relating to those activities for which it is

responsible;

(e) alert the competent authorities of another Member

State when they observe incorrect information in the

EU Tissue Establishment Compendium relating to the

other Member State or when they observe a situation

of significant non-compliance with the provisions

relating to the Single European Code relating to the

other Member State;

(f)

alert the Commission and the other competent

authorities when in their assessment the EU Tissue and

Cell Product Compendium requires an update.

(3) The application of the Single European Code does not

preclude the additional application of other codes in accordance

with the requirements set out under any other relevant law.

Tissues and cells already in storage on 29 October 2016

shall be exempted from the obligations relating to the Single

European Code, provided the tissues and cells are released for

circulation in the Union within five years following that date and

under the condition that full traceability is ensured by alternative

means. For tissues and cells which remain in storage and which are

only released for circulation after the expiry of this five-year period

and for which the application of the Single European Code is not

possible, in particular because the tissues and cells are stored under

deep-freeze conditions, the tissue establishments shall use the

procedures applicable to products with small labels as laid down in

regulation 13(1)(f).