Commission Directive 2006/86/EC of 24 October 2006 implementing Directive 2004/23/EC of the European Parliament and of the Council as regards traceability requirements, notification of serious adverse reactions and events and certain technical requirements for the coding, processing, preservation, storage and distribution of human tissues and cells   (Text with EEA relevance)
Date: 2006-10-24
Institutions: European Commission
Subjects: cytology, exchange of information, public health, quality standard, safety standard, traceability

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COMMISSION DIRECTIVE 2006/86/EC

of 24 October 2006

implementing Directive 2004/23/EC of the European Parliament and of the Council as regards
traceability requirements, notification of serious adverse reactions and events and certain
technical requirements for the coding, processing, preservation, storage and distribution of
human tissues and cells

(Text with EEA relevance)

THE COMMISSION OF THE EUROPEAN COMMUNITIES,

Having regard to the Treaty
Community,

establishing the European

the European
Having regard to Directive 2004/23/EC of
Parliament and of the Council of 31 March 2004 on setting
standards of quality and safety for the donation, procurement,
testing, processing, preservation, storage and distribution of
human tissues and cells (1), and in particular Article 8,
Articles 11(4) and 28(a), (c), (g) and (h) thereof,

Whereas:

(1)

(2)

(3)

Directive 2004/23/EC lays down standards of quality and
safety for the donation, procurement, testing, processing,
preservation, storage and distribution of human tissues
and cells intended for human applications, and of manu-
factured products derived from human tissues and cells
intended for human applications, so as to ensure a high
level of human health protection.

In order to prevent
the transmission of diseases by
human tissues and cells for human applications and to
ensure an equivalent level of quality and safety, Directive
2004/23/EC calls
specific
technical requirements for each one of the steps in the
human tissues and cells application process,
including
standards and specifications with regard to a quality
system for tissue establishments.

establishment of

the

for

An accreditation, designation, authorisation or licensing
system for tissue establishments and for the preparation
processes at the tissue establishments should be estab-
lished in Member States in accordance with Directive
2004/23/EC, in order to ensure a high level of protection
of human health.
is necessary to lay down the
technical requirements for this system.

It

(4)

The requirements for accreditation, designation, authori-
sation or licensing of tissue establishments should cover
the organisation and management, personnel, equipment

(1) OJ L 102, 7.4.2004, p. 48.

and materials,
records
authorised or
comply with additional
activities they carry out.

facilities/premises, documentation and
and quality review. Accredited, designated,
should
establishments
requirements for the specific

licensed tissue

The air quality standard during the processing of tissues
and cells is a key factor that may influence the risk of
tissue or cell contamination. An air quality with particle
counts and microbial colony counts equivalent to those
of Grade A, as defined in the European Guide to Good
Manufacturing Practice, Annex 1 and Commission
2003/94/EC (2),
Directive
required.
However,
in certain situations, an air quality with
particle counts and microbial colony counts equivalent
to those of Grade A standard is not indicated. In these
should be demonstrated and docu-
circumstances
mented that
the
quality and safety required for the type of tissue and
cells, process and human application concerned.

chosen environment achieves

generally

it
the

is

The scope of this Directive should embrace the quality
and safety of human tissues and cells during coding,
processing, preservation, storage and distribution to the
healthcare establishment where they will be applied to
the human body. However, it should not extend to the
human application of these tissues and cells (such as
implantation
or
transfer of embryos). The provisions of this Directive
serious
concerning traceability and the reporting of
adverse
also to the
donation, procurement and testing of human tissues
and
Directive
by
2006/17/EC (3).

insemination

Commission

perfusion,

regulated

reactions

surgery,

events

apply

cells

and

The use of tissues and cells for human application carries
a risk of disease transmission and other potential adverse
effects in recipients. In order to monitor and reduce these
effects,
traceability and a
Community procedure for notifying serious adverse
reactions and events should be set out.

requirements

specific

for

(5)

(6)

(7)

(2) http://pharmacos.eudra.org/F2/eudralex/vol-4/home.htm and OJ L 262,

14.10.2003, p. 22.

(3) OJ L 38, 9.2.2006, p. 40.

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(8)

(9)

Suspected serious adverse reactions, in the donor or in
the recipient, and serious adverse events from donation
to distribution of tissues and cells, which may influence
the quality and safety of tissues and cells and which may
be attributed to procurement (including donor evaluation
and selection), testing, processing, preservation, storage
and distribution of human tissues and cells should be
notified without delay to the competent authority.

(a) human tissues and cells intended for human applications;

and

(b) manufactured products derived from human tissues and
those

intended for human applications, where

cells
products are not covered by other directives.

to

and

Serious adverse reactions may be detected during or
following procurement
in living donors or during or
following human application. They should be reported
for subsequent
to the associated tissue establishment
investigation
competent
the
notification
authority. This should not preclude a procurement orga-
nisation or an organisation responsible for human appli-
competent
cation from also directly notifying the
authority if it so wishes. This Directive should define
the minimum data needed for notification to the
competent authority, without prejudice to the ability of
Member States to maintain or introduce in their territory
more stringent and protective measures which comply
with the requirements of the Treaty.

The provisions of Articles 5 to 9 of

2.
this Directive,
concerning traceability and the reporting of serious adverse
also apply to the donation,
shall
reactions
procurement and testing of human tissues and cells.

and events

Article 2

Definitions

For the purposes of this Directive, the following definitions
apply:

(10)

In order to minimise transmission costs, avoid overlaps
and increase administrative efficiency, modern tech-
nologies and e-government solutions should be used to
perform the tasks
related to the transmission and
treatment of information. These technologies should be
based on a standard exchange format using a system
suitable for the management of reference data.

(a)

‘reproductive cells’ means all tissues and cells intended to be
used for the purpose of assisted reproduction;

(b) ‘partner donation’ means the donation of reproductive cells
between a man and a woman who declare that they have an
intimate physical relationship;

(11)

To facilitate traceability and information on the main
characteristics and properties of tissues and cells,
it is
necessary to lay down the basic data to be included in
a single European code.

(c)

‘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;

(12)

This Directive respects
rights and
observes the principles recognised in particular by the
Charter of Fundamental Rights of the European Union.

the fundamental

(d)

‘quality management’ means the coordinated activities to
direct and control an organisation with regard to quality;

(13)

in this Directive are in
The measures provided for
accordance with the opinion of the Committee set up
by Article 29 of Directive 2004/23/EC,

(e)

Procedures’

‘Standard Operating
(SOPs) means written
instructions describing the steps
in a specific process,
including the materials and methods to be used and the
expected end product;

HAS ADOPTED THIS DIRECTIVE:

Article 1

Scope

This Directive shall apply to the coding, processing,

1.
preservation, storage and distribution of:

(f)

(or ‘qualification’

‘validation’
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 consis-
tently produce a product meeting its predetermined specifi-
cations and quality attributes; a process is validated to
evaluate the performance of a system with regard to its
effectiveness based on intended use;

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(g)

testing and storage,

‘traceability’ means the ability to locate and identify the
tissue/cell during any step from procurement,
through
processing,
to distribution to the
recipient or disposal, which also implies the ability to
identify the donor and the tissue establishment or the
manufacturing facility receiving, processing or storing the
tissue/cells, and the ability to identify the recipient(s) at
the medical facility/facilities applying the tissue/cells to the
recipient(s); traceability also covers the ability to locate and
identify all relevant data relating to products and materials
coming into contact with those tissues/cells;

(h) ‘critical’ means potentially having an effect on the quality
and/or safety of or having contact with the cells and tissues;

(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
adverse
how that organisation should report
reactions as referred to in (b).

serious

(i)

(j)

‘procurement organisation’ means a health care establishment
or a unit of a hospital or another body that undertakes the
procurement of human tissues and cells and that may not
be accredited, designated, authorised or licensed as a tissue
establishment;

2. Member States shall ensure that tissue establishments:

‘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.

(a) have procedures in place to communicate to the competent
authority without delay all relevant available information
about suspected serious adverse reactions as referred to in
paragraph 1(a) and (b);

Article 3

Requirements for the accreditation, designation,
authorisation or licensing of tissue establishments

A tissue establishment must comply with the requirements set
out in Annex I.

Article 4

Requirements for the accreditation, designation,
authorisation, licensing of tissue and cell preparation
processes

Preparation processes at the tissue establishments must comply
with the requirements set out in Annex II.

(b) have procedures in place to communicate to the competent
authority without delay the conclusion of the investigation
to analyse the cause and the ensuing outcome.

3. Member States shall ensure that:

(a)

the responsible person referred to in Article 17 of Directive
2004/23/EC notifies the competent authority of the infor-
mation included in the notification set out in Part A of
Annex III;

Article 5

Notification of serious adverse reactions

1. Member States shall ensure that:

(b) tissue establishments notify the competent authority of the
actions taken with respect to other implicated tissues and
cells that have been distributed for human applications;

(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;

(c)

tissue establishments notify the competent authority of the
conclusion of the investigation, supplying at least the infor-
mation set out in Part B of Annex III.

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Article 6

Notification of serious adverse events

1. Member States shall ensure that:

(a) procurement organisations and tissue establishments 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;

Article 7

Annual reports

1. Member States shall submit to the Commission an annual
report, by 30 June of the following year, on the notification of
serious adverse reactions and events received by the competent
to the competent
authority. The Commission shall submit
the reports
authorities of Member States a summary of
report
received. The competent authority shall make this
available to tissue establishments.

(b) organisations responsible for human application of tissues
and cells have procedures in place to notify tissue estab-
lishments without delay of any serious adverse events that
may influence the quality and safety of the tissues and cells;

Data transmission shall comply with the data exchange
2.
format specifications as set out in Annex V, part A and B,
and shall provide all the information necessary to identify the
sender and maintain its reference data.

(c)

tissue establishments provide to the organisation responsible
for human application information about how that organi-
sation should report serious adverse events to them that
may influence the quality and safety of the tissues and cells.

2.
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
competent authority.

3. Member States shall ensure that tissue establishments:

(a) have procedures in place to communicate to the competent
authority without delay all relevant available information
about suspected serious adverse events as referred to in
paragraph 1(a) and (b);

Article 8

Communication of information between competent
authorities and to the Commission

Member States shall ensure that
their competent authorities
communicate to each other and to the Commission such infor-
mation as is appropriate with regard to serious adverse reactions
and events,
in order to guarantee that adequate actions are
taken.

Article 9

Traceability

1.
Tissue establishments shall have effective and accurate
systems to uniquely identify and label cells/tissues received
and distributed.

(b) have procedures in place to communicate to the competent
authority without delay the conclusion of the investigation
to analyse the cause and the ensuing outcome.

2.
Tissue establishments and organisations responsible for
human application shall retain the data set out in Annex VI
in an appropriate and readable storage
for at least 30 years,
medium.

4. Member States shall ensure that:

(a)

the responsible person referred to in Article 17 of Directive
2004/23/EC notifies the competent authority of the infor-
mation included in the notification set out in Part A of
Annex IV;

(b) tissue establishments evaluate serious adverse events to

identify preventable causes within the process;

Article 10

European coding system

1.
A single European identifying code shall be allocated to all
donated material at the tissue establishment, to ensure proper
identification of the donor and the traceability of all donated
material and to provide information on the main characteristics
and properties of tissues and cells. The code shall incorporate at
least the information set out in Annex VII.

(c)

tissue establishments notify the competent authority of the
conclusion of the investigation, supplying at least the infor-
mation set out in Part B of Annex IV.

Paragraph 1 shall not apply to partner donation of repro-

2.
ductive cells.

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Article 11

Transposition

Article 12

Entry into force

1. Member States shall bring into force the laws, regulations
and administrative provisions necessary to comply with this
Directive by 1 September 2007, at
the latest. They shall
forthwith communicate to the Commission the text of those
provisions and a correlation table between those provisions and
this Directive.

Member States shall bring into force the laws, regulations and
administrative provisions necessary to comply with Article 10
of this Directive, by 1 September 2008.

When Member States adopt those provisions, they shall contain
a reference to this Directive or be accompanied by such a
reference on the occasion of their official publication. Member
States shall determine how such reference is to be made.

2. Member States shall communicate to the Commission the
text of the main provisions of national law which they adopt in
the field covered by this Directive.

This Directive shall enter into force on the 20th day following
its publication in the Official Journal of the European Union.

Article 13

Addressees

This Directive is addressed to the Member States.

Done at Brussels, 24 October 2006.

For the Commission

Markos KYPRIANOU
Member of the Commission

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ANNEX I

Requirements for accreditation, designation, authorisation or licensing of tissue establishments as referred to in
Article 3

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/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/designa-

tion/authorisation or licensing is sought, in accordance with the standards laid down in this Directive.

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 estab-
lishment.

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/licensing is sought.

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.

B. PERSONNEL

2. All personnel should have clear, documented and up-to-date job descriptions. Their tasks, responsibilities and account-

ability must be clearly documented and understood.

3. Personnel must be provided with initial/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/technical processes and principles relevant to their

designated tasks;

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(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.

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.

C. EQUIPMENT AND MATERIALS

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 (1) and Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on in
vitro diagnostic medical devices (2).

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

the activities for which accreditation/designa-

tion/authorisation or licensing is sought, in accordance with the standards laid down in this Directive.

D. FACILITIES/PREMISES

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;

(b) or, 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;

(1) OJ L 169, 12.7.1993, p. 1. Directive as last amended by Regulation (EC) No 1882/2003 of the European Parliament and of the Council

(OJ L 284, 31.10.2003, p. 1).

(2) OJ L 331, 7.12.1998, p. 1. Directive as amended by Regulation (EC) No 1882/2003.

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(c) or, where it is demonstrated that the mode and route of application of the tissue or cell to the recipient implies a
infection to the recipient than with cell and tissue

significantly lower risk of transmitting bacterial or fungal
transplantation;

(d) or, 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
including relevant

and cells, the storage conditions necessary to maintain the required tissue and cell properties,
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 demon-

strate 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/licensing is sought. Documents must be regularly reviewed and must conform to the standards laid down
in this Directive. 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 imple-

mented 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 10 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.

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F. QUALITY REVIEW

1. An audit system must be in place for the activities for which accreditation/designation/authorisation/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.

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ANNEX II

Requirements for the authorisation of tissue and cell preparation processes at the tissue establishments as
referred to in Article 4

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 Annex.

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/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 in this Directive, accordingly with Annex 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/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 in this Directive 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.

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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/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 retrieve 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,
applicable;

identification number or code of the tissue/cells, and lot or batch number where

(b) identification of the tissue establishment;

(c) expiry date;

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(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.

If any of the information under points (d) and (e) 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 Articles 5 to 6;

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

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).

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ANNEX III

NOTIFICATION OF SERIOUS ADVERSE REACTIONS

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ANNEX IV

NOTIFICATION OF SERIOUS ADVERSE EVENTS

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ANNEX V

ANNUAL NOTIFICATION FORMAT

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ANNEX VI

Information on the minimum donor/recipient data set to be kept as required in Article 9

A. BY TISSUE ESTABLISHMENTS

Donor identification

Donation identification that will include at least:
— Identification of the procurement organisation or Tissue establishment
— Unique Donation ID number
— Date of procurement
— Place of procurement
— Type of donation (e.g. single v multi-tissue; autologous v allogenic; living v deceased)

Product identification that will include at least:
— Identification of the tissue establishment
— Type of tissue and cell/product (basic nomenclature)
— Pool number (if applicable)
— Split number (if applicable)
— Expiry date
— 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

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

(a) Identification of the supplier tissue establishment

(b) Identification of the clinician or end user/facility

(c) Type of tissues and cells

(d) Product identification

(e) Identification of the recipient

(f) Date of application

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ANNEX VII

Information contained in the European Coding System

(a) Donation identification:
— Unique ID number
— Identification of the tissue establishment

(b) Product identification:

— Product code (basic nomenclature)
— Split number (if applicable)
— Expiry date