337 tal-2007 - Regolamenti tal-2007 dwar Tessuti u Ċelloli Umani (Kodifikazzjoni, Ipproċessar, Preservazzjoni, Ħżin u Distribuzzjoni)

L.N. 337 of 2007

HUMAN BLOOD AND TRANSPLANTS ACT

(CAP. 483)

Human Tissues and Cells (Coding, Processing, Preservation,

Storage and Distribution) Regulations, 2007

BY virtue of article 16 of the Human Blood and Transplants Act,

the Minister of Health, the Elderly and Community Care has made the

following regulations:-

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

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

Regulations, 2007.

(2) (a) 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) Regulations 1 to 9 shall come into force on the 1 st

September, 2007 and regulation 10 shall come into force on the 1 st

September, 2008.

(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 [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].

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] 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,

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

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.

(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.

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).

Mitbug[ fl-Istamperija tal-Gvern — Printed at the Government Printing Press

Lm1.04 (€2.42)

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;

“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;

“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;

“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;

“reproductive cells” means all tissues and cells intended to

be used for the purpose of assisted reproduction;

“Standard Operating Procedures” (SOPs) means written

instructions describing the steps in a specific process, including

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

“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

at the medical facilities applying the tissue or cells to the 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;

“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.

A tissue establishment shall, for the purposes of its Requirements for

the accreditation,

accreditation, designation, authorisation or licensing, comply with the etc. of tissue

establishments.

requirements set out in Schedule I to these regulations.

Preparation processes at the tissue establishments shall, for Requirements for

the accreditation,

the purposes of its accreditation, designation, authorisation or licensing, etc. of tissue and

comply with the requirements set out in Schedule II to these regulations. cell preparation

processes.

Notification of

(1) The Authority shall ensure that

serious adverse

reactions.

(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) hereof.

(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 paragraphs (a) and

(b) of sub-regulation (1) hereof; 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 to these regulations;

(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 to these

regulations.

(1) 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.

(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 Authority.

(3) 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

paragraphs (a) and (b) of sub-regulation (1) hereof;

(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.

(4) (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 to these

regulations;

(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 to these regulations.

(1) The Authority shall submit to the Commission an annual Annual reports.

report, by the 30 th 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 to these regulations, Parts

A and B, and shall provide all the information necessary to identify the

sender and maintain its reference data.

(1) Tissue establishments shall have effective and accurate Traceability.

systems to uniquely identify and label cells or tissues received and

distributed.

(2) Tissue establishments and organisations responsible for

human application shall retain the data set out in Schedule VI to these

regulations for at least thirty years, in an appropriate and readable storage

medium.

(1) In order 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 tissue and cells, tissue

establishments shall allocate a single European identifying code to all

donated material.

(2) The code shall incorporate at least the information set

out in Schedule VII to these regulations.

(3) The provisions of sub-regulations (1) and (2) shall not

apply to partner donation of reproductive cells.

10.2003, p. 1).

[2] OJ L 331, 7.12.1998, p. 1. Directive as amended by Regulation (EC) No

1882/2003.