Tuesday, August 22, 2017
Project co-funded by the European Commission in the framework of the 2nd Health Programme
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A.5.1. ACTIVITIES

A.5.1.1. Reception

1. TEs shall ensure that all donations of human tissues and cells are subjected to tests in accordance with the requirements established and that the selection and acceptance of tissues and cells comply with them.

2. TEs shall ensure that human tissue and cells and associated documentation comply with the requirements established.

3. TEs shall verify and record the fact that the packaging of human tissue and cells received complies with the requirements established. All tissues and cells that do not comply with those provisions shall be discarded.

4. The acceptance or rejection of received tissues/cells shall be documented.

5. TEs shall ensure that human tissues and cells are correctly identified at all times. Each delivery or batch of tissues or cells shall be assigned an identifying code.

6. Tissue and cells shall be held in quarantine until such time as the requirements relating to donor testing and information have been met.[1]

7. The competent authority or authorities shall ensure that the tissue and/or cell donation and procurement procedures and the reception of tissues and/or cells at the tissue establishment comply with the requirements set out.[2]

A.5.1.1.1. Receipt of tissues and cells at processing centre

1. When the retrieved tissues/cells arrive at the tissue establishment, there must be documented verification that the consignment, including the transport conditions, packaging, labelling and associated documentation and samples, meet the requirements and the specifications of the receiving establishment.

2. Each establishment must ensure that the tissue and cells received are quarantined until they, along with the associated documentation, have been inspected or otherwise verified as conforming to requirements.  The review of relevant donor/procurement information and thus acceptance of the donation needs to be carried out by specified/authorised persons.

3. Each tissue establishment must have a documented policy and specifications against which each consignment of tissues and cells, including samples, are verified.  These must include the technical requirements and other criteria considered by the tissue establishment to be essential for the maintenance of acceptable quality.  The tissue establishment must have documented procedures for the management and segregation of non-conforming consignments, or those with incomplete test results, to ensure that there is no risk of contamination of other tissues and cells being processed, preserved or stored.

4. The data that must be registered at the tissue establishment (except for donors of reproductive cells intended for partner donation) include:

a)    consent/authorisation; including the purpose(s) for which the tissues and cells may be used (i.e. therapeutic or research, or both therapeutic use and research) and any specific instructions for disposal if the tissue or cells are not used for the purpose for which consent was obtained

b)    all required records relating to the procurement and the taking of the donor history, as described in the donor documentation section

c)     results of physical examination, of laboratory tests and of other tests (such as the autopsy report)

d)    for allogeneic donors, a properly documented review of the complete donor evaluation against the selection criteria by an authorised and trained person

e)     in the case of cell cultures intended for autologous use, documentation of the possibility of medicinal allergies (such as to antibiotics) of the recipient.[3]

5. The TE, or ORHA and TE, should sign an agreement defining the responsibilities of each party in the transport of the tissues/cells to the tissue establishment.

6. Such transportation must be direct, without intermediate stops when possible, to ensure the safety and maintenance of the temperature conditions of the tissues and cells.

A.5.1.1.2. Verification of tissues received

1. Upon the reception of tissues and cells by the TE, the recovered material, the human samples (including blood) and the accompanying documentation must be identified and verified.

2. The documents accompanying this human material must be checked to ensure they contain all relevant information relating to the donation and sampling.  During reception of the documentation, the correspondence between the packing list or shipping record is verified with the contents of the package.

3. The packaging and material obtained and the accompanying human samples should be examined to ensure that the quality of this material has not been altered in transit, checking and recording:

a)     The identification as listed in the packing list or shipping record;

b)    No evidence of opening or manipulation exists;

c)     No signs of damage which may result in the deterioration of tissues or storage problems;

d)    Number of donor;

e)     Recovery date and time;

f)     Tissue for transplant / research;

g)     Source / destination;

h)    Tissues/cells description;

i)      Storage temperature;

j)      Status of the tissue (e.g. quarantine).

4. There should be a procedure in place to manage any discrepancy or non-conformity that might appear.

5. During this physical and documental reception, the tissues and cells should be stored in defined, separated and adequate location and conditions.

A.5.1.1.3. Identification of tissues and cells

1. Upon reception of the tissues and cells by the TE, a unique identification code should be assigned to the material recovered.  This code is then completed to identify the different products and batches obtained during processing and storage.

This code should allow traceability and a formal and unambiguous identification of all tissues and cells from recovery to transplantation (including all stages of processing, storage and distribution).

2. This code will be present on the label of tissues and cells at each stage of processing and storage as well as on any documentation that relates to these tissues and cells.

The label will include, at least, the following information:

a)     Unique identification donor number (original coding);

b)    Identification of the tissue bank;

c)     Identification of the product;

d)    Batch number, if applicable.

3. A unique identifying code shall be allocated to the donor and the donated tissues and cells, during procurement or at the tissue establishment, to ensure proper identification of the donor and the traceability of all donated material.  The coded data shall be entered in a register maintained for the purpose.[4]

 

A.5.1.2. Access to the processing facilities

1. The flows of entry, transit and exit of personnel and material through the processing area and the rules of use and clothing in them should be established in order to:

a)     Minimize the risk of tissues/cells contamination

b)    Reducing the environmental bioburden

c)     Protect the staff of biohazards

2. A written procedure designed to eliminate potential contamination and / or cross contamination from personnel and materials to tissues and cells should be in place.

3. The entrance of personnel, tissue/cells and materials should be done through airlocks avoiding the direct flow of non-treated air into the cleanrooms.

4. Personnel gowning procedures should be sufficiently validated to ensure that both, gowning materials and systematic are adequate and the resulting microbial monitoring of the clothes are satisfactory.

5. The materials and tissues/cells packages should enter the facilities using a validated procedure where the cleanliness level, according to the microbial load, conforms to the destination cleanroom.

6. Personnel involved in processing should be the minimum number required for efficient planned procedures.  Additional persons present in processing areas should be taken into account during risk assessment when the procedure is designed.

A.5.1.3. Processing

A.5.1.3.1. General

1. TEs shall include in their standard operating procedures all processes that affect quality and safety and shall ensure that they are carried out under controlled conditions.  TEs shall ensure that the equipment used, the working environment and process design, validation and control conditions are in compliance with the requirements established.

2. Any modifications to the processes used in the preparation of tissues and cells shall also meet the criteria laid down in the corresponding change control procedure.

3. TEs shall include in their standard operating procedures special provisions for the handling of tissues and cells to be discarded, in order to prevent the contamination of other tissues or cells, the processing environment or personnel.[5]

4. Every step of processing is performed under defined conditions to guarantee the quality of tissues and cells and the security of the staff.

5. Preparation methods include: transformation processes, the necessary equipment and material, media preparation, additional therapeutic products used and the controls performed.

6. The requirements for personnel, premises and equipment have been developed in previous sections, as well as those on the quality control and documentation.

7. If the processing is done by a third party, a written agreement is needed between the TE and the subcontracted party.

8. The time limits between recovery, processing and storage are determined and reflected in the tissue specific GTPs.  When appropriate, these maximum times from recovery (or cardiac arrest) until processing and storage are defined.  The recovery, processing and storage time is written in the dossier of those tissues and cells.

9. The evaluation quality controls performed to the tissues/cells should be established and each of them should be described in written procedures.

10. The written procedures should at least include the testing method, the sample size and the accepted criteria.

11. The minimum evaluation requirements for each type of tissue/cells are described in the specific section.

12. Should in-process controls be performed in the processing area, they should be carried out ensuring that no risk is affecting the processing itself.

A.5.1.3.2. Processing methods

Processing methods should be designed to ensure both safety and biological functionality of a prepared tissue graft.  Methods of processing should be validated (See validation).

A.5.1.3.3. Cross contamination 

1. In order to avoid cross-contamination, the tissues from one donor should not enter at any time during processing or during storage into contact with tissues from another donor.

 2. Furthermore, the grafts that must be further processed (e.g. lyophilisation, sterilization etc.) should be treated as single donors.  Each tissue should have a batch number that is also mentioned in the dossier.

3. Processing techniques are critically assessed at regular intervals to ensure they always provide the desired results.

4. Non-conforming products must be identified and separated from compliant products.

5. The treatment of non-compliant products will be decided by the responsible person in charge of the tissue bank.

A.5.1.4. Quality Control

1. The evaluation quality controls performed on the tissues/cells should be established and each should be described in written procedures.

2. The written procedures should at least include the method of the test, the sample size and the accepted criteria.

3. The minimum evaluation requirements for each type of tissue/cells are described in the specific section.

4. Should in-process controls be performed in the processing area, they should be carried out ensuring that no risk affects the processing itself.

 

A.5.1.4.1. Microbiological control
A.5.1.4.1.1. General Principle

1. The microbiological safety of tissues and cells is based on:

a)     Donor selection and the absence of initial contamination;

b)    Control and monitoring of contamination during the process;

c)     Donor environment process (Quality Control-IPC) validated methods of decontamination, sterilization or inactivation during processing of tissues and cells;

d)    Bacteriological examinations carried out at different stages of the process.

A.5.1.4.1.2. Microbiological controls

1. Microbiological tests must focus on aerobic and anaerobic as well as fungi.  If risk factors are present, it is desirable to perform additional tests for detection of mycoplasma.

2. It must be made on:

a)     The starting or incoming tissue;

b)    The tissue immediately prior to final packaging;

c)     When applicable, after a stage of decontamination or sterilization (direct control or monitoring control).

3. Various procedures exist for securing microbiological control, such as decontamination by antibiotics, sterilization, or any other physicochemical methods.  These procedures must be specifically adapted to the type of tissue or cells and should be validated in detail.  

A.5.1.5. Packaging and labelling

1. Premises for the packaging of tissues/cells should be specifically designed and laid out so as to avoid mix-ups or cross-contamination.[6]

2. TEs shall ensure that labelling, documentation and packaging conform to the requirements referred to in the tissue specific sections.

3. When applicable, reconciliation of labels edited, used and returned / rejected should be performed according to written procedures.

5. All excess labels containing quality information should be destroyed or maintained in a secure manner, when necessary, to prevent cross contamination or mix-ups.

6. Obsolete labels should be destroyed according to written procedures.

7. Printed labels should be carefully examined to ensure that information contained conforms to the corresponding tissue/cells.  The results of this examination should be documented.

8. A printed label, representative of those used, should be included in the processing records.

9. Labelling and packaging operations should be designed to prevent any cross contamination or mix-ups.  Simultaneous operations should be avoided or adequate measures should be taken to ensure no cross contamination or mix-ups occur.

10. Facilities where packaging or labelling operations have taken place should be inspected and documented before starting any other operation so as to guarantee that all the previous materials have been removed.

A.5.1.5.1. Packaging and labelling materials management

1. There should be written procedures describing: the receipt, identification, quarantine, sampling, examination and/or testing and release, and handling of packaging and labelling materials.

2. Records should be maintained for each shipment of labels and packaging materials showing receipt, examination, or testing, and whether accepted or rejected.

3. Containers should provide adequate protection against deterioration or contamination of the tissues/cells, that may occur during the storage and transportation conditions, and resist the preparation techniques used (e.g. sterilization).  A validation study should be done.

4. Containers should be clean and sanitized to ensure that they are suitable for their intended use.  These containers should not alter the quality, safety and efficacy of the tissues/cells.

5. Labels should be designed to adhere firmly to the container under all storage and transport conditions and the preparations techniques used.  A validation study should be done.

A.5.1.5.2. Primary packaging and labelling operation

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)    If applicable, the fluid in which the tissue is preserved.

2. 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.

3. 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 Biovigilance B.6;

i)      presence of potential harmful residues (e.g. antibiotics, ethylene oxide etc.).[7]

A.5.1.5.3. Secondary packaging and labelling operation

1. 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);

g)    Expiry date;[8]

h)    Identification of the tissue, donor identification number, type of tissue or cells, and batch number if applicable;

i)      The words ‘AUTOLOGOUS USE’ and the recipient's identification in case of autologous donation;

j)      The recipient's identification in case of directed donation.

A.5.1.6. Documentation and release in distribution

A.5.1.6.1. General

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 text.  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 TEs 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.[9]

7. A validation study should be performed to show the effectiveness of the processing procedures.  Procedures should be written identifying the key aspects to be considered and they should include but not limited to:

a)     Access to the processing area;

b)    Gowning requirements;

c)     Measures to prevent contamination from the facilities, operators and materials;

d)    Cleanrooms and equipment qualification and calibration;

e)     Microbial and airborne routine monitoring;

f)     Materials used during processing;

g)     Critical processing steps;

h)    Tissues/cells specifications;

i)      Quality controls, analytical methods and acceptance criteria;

j)      Sampling plan;

k)    Packaging and labelling materials, literature and operations;

l)      Transport validation (include time period from initial packaging to destination arrival).

7. Generally, it is considered as acceptable that three consecutive processes within the finally agreed parameters would constitute a validation of the process.

A.5.1.6.2. Release

1. The items indicated in the Processing File Contents (see A.5.1.6.3) should be required for the release or rejection of the tissues/cells and thus should be documented.  The processing dossier should include the contents shown in the Processing File Contents section.

2. The responsible person for Processing should make and sign a statement, which specifies the fulfilment of all ethical and legal requirements, releasing the tissue/cells for transplant or investigation.  When any evaluation is pending at the moment of the release, the statement should mention specifically that it is a partial release and that the results and final release will be conveyed in writing, as soon as technically possible.

A.5.1.6.3. Processing File Contents

1. The Processing File will contain at least:

a)     The Recovery File and/or release statement of Recovery Responsible Person;

b)    Type of tissues and cells processed and / or stored;

c)     Quantitative and qualitative description of tissues and cells processed, preserved and / or stored;

d)    Date and time of each stage of processing and storage, the identification of persons responsible for each step and the identifying media and related products used (Batch Number and expiry date);

e)     Status of tissues and cells at all stages of processing and storage (i.e. quarantine, released for therapeutic use, in vitro research, etc.);

f)     Use of antibiotics, antibiotic composition; incubation period. if applicable;

g)     Type and amount of media used;

h)    Procedures and records concerning the processing of tissues and cells, if applicable;

i)      Processing data (preparation, culture technique, incubation, treatment chemicals;

j)      Data on the conservation (i.e cryopreservation, tracing the curve of cooling, glycerolisation, lyophilisation, etc.);

k)    Data on techniques of decontamination, sterilization and viral inactivation;

l)      Results of specific quality test depending on tissues and cells type (e.g. HLA, histology, radiology results, cell viability or tissue, etc.);

m)   Procedures and records concerning the preservation of tissues and cells, if applicable;

n)    Date and time of storage;

o)    Method of storage;

p)    Storage temperature;

q)    Expiring date;

r)     Identification of tissues and cells: Donor identification code (ID) + product code.

Access to registers and data must be restricted to persons authorised. This File must be kept for a minimum of 30 years after clinical use.

A.5.1.6.4. Availability for inspection

1. The records must be accessible at any time for inspections conducted by the competent authority.  Donor identity and data related to it will be restricted to the TE but must, if necessary, be available for inspectors.

A.5.1.6.5. Traceability

1. The TE must guarantee that the establishment, institution or surgeon to whom the tissue or cells are delivered is able to ensure traceability: it should be embodied in a document or written agreement with explicit traceability conditions.

2. The dossier must ensure the traceability of tissues and cells processed by the bank.

3. Traceability must be ensured from donor to recipient (or until the removal of tissues or cells concerned) and vice versa.  The traceability of the donor up to distribution is the responsibility of the TE, while traceability from reception of the tissue or cells up to its use is the responsibility of the institution that receives it.

4. The establishment receiving the tissues and cells should record:

a)     Identification of the human material;

b)    TEs providing the material;

c)     The final destination (distribution, delivery and implementation in a recipient or disposal);

d)    Identification of recipient;

e)     The date of implantation.

5. The traceability requirements apply to all relevant data related to products and materials that may come into contact with these tissues and cells.

7. Corrections, changes or amendments made to a file should be carried out according to a written change control management procedure.

8. When electronic data is affected, any critical change should be recorded and available through an audit trail.

9. TEs shall have effective and accurate systems to uniquely identify and label cells/tissues received and distributed.

11. 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.[10]  The code shall incorporate at least:

a)    Donation identification;

                        i.     Unique ID number

                       ii.     Identification of the tissue establishment

b)    Product identification;

                        i.     Product code (basic nomenclature)

                       ii.     Split number (if applicable)

                     iii.     Expiry date.[11]

 



[1] Directive 2004/23/EC of the European Parliament and of the Council (Art.19)

[2] Commission Directive 2006/17/EC ( Art.5)

[3] Commission Directive 2006/17/EC ( Annex IV)

[4] Commission Directive 2006/17/EC (Art.2)

[5] Directive 2004/23/EC of the European Parliament and of the Council ( Art.20)

[6] EU Good Manufacturing Practices Guidelines

[7] Commission Directive 2006/86/EC (Annex II)

[8] Commission Directive 2006/86/EC (Annex II)

[9] Commission Directive 2006/86/EC (Annex I)

[10] Commission Directive 2006/86/EC (Art.10)

[11] Commission Directive 2006/86/EC (Annex VII)

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