Tuesday, September 19, 2017
Project co-funded by the European Commission in the framework of the 2nd Health Programme
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A.7.1. QUALITY ASSURANCE

A.7.1.1. General

1. Member States shall take all necessary measures to ensure that each tissue establishment puts in place and updates a quality system based on the principles of good practice.[1]

2. Any person involved in the process is responsible for quality.  The management must have a systematic approach to quality assurance and to the implementation and maintenance of quality assurance system.

3. The quality system includes quality assurance, quality control and continuous improvement of quality, personnel, facilities, equipment, documentation, recovery, donor selection, testing, preservation, storage, distribution, the recall of tissues and cells, the external and internal auditing, contract management, non-compliance and self-inspection.

4. The quality assurance system guarantees that all critical procedures are described in SOP's and are performed according to them.  The effectiveness of the system is periodically evaluated by the management.

5. The quality system appropriate for the processing of tissues and cells should ensure that:

a)   Tissues and cells are designed and developed in a way that takes account of the requirements of good tissue practices (GTP);

b)   Processing and operations are clearly specified and good tissue practice adopted;

c)   Managerial responsibilities are clearly specified;

d)   Arrangements are made for the processing, supply and use of the correct starting and packaging materials;

e)   All necessary controls on intermediate phases and in-process controls, and validations are carried out;

f)    The finished tissues and cells are correctly processed and checked, according to the defined procedures;

g)   Tissues and cells are not sold or supplied before the responsible person, or a person authorized by a responsible person has certified that each tissue / cells have been processed and controlled in accordance with the requirements of the Establishment Authorisation and any other regulations relevant to the processing, control and release of tissues and cells;

h)   Satisfactory arrangements exist to ensure, as far as possible, that the tissues and cells are stored, distributed and subsequently handled so that quality is maintained throughout their shelf life;

i)    There is a procedure for self-inspection and/or quality audit which regularly appraises the effectiveness and applicability of the quality assurance system.

 

A.7.1.2. Documentation

1. There must be a system in place that results in clearly defined and effective documentation, correct records and registers and authorised 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.[2]

7. The documentation system must assure that:

a)     All processing operations are clearly defined, systematically reviewed in the light of experience and shown to be capable of consistently process tissues and cells of the required quality and complying with their specifications;

b)    Critical steps of processing and significant changes to the processes are validated;

c)     All necessary facilities for GTP are provided including:

                        i.     Appropriately qualified and trained personnel;

                       ii.     Adequate premises and space;

                     iii.     Suitable equipment and services;

                     iv.     Correct materials, containers and labels;

                       v.     Approved procedures and instructions;

                     vi.     Suitable storage and transport

d)    Instructions and procedures are written in an instructional form in clear and unambiguous language, specifically applicable to the facilities provided;

e)     Operators are trained to carry out procedures correctly;

f)     Records are made, manually and/or by recording instruments, during processing which demonstrate that all the steps required by the defined procedures and instructions were in fact taken and that the quantity and quality of the tissues and cells was as expected.  Any significant deviations are fully recorded and investigated;

g)     Records of processing including distribution, which enable the complete history of a tissue/cells (see traceability section) to be traced, are retained in a comprehensible and accessible form;

h)    The distribution of the tissues and cells minimises any risk to their quality;

i)      A system is available to recall any tissue / cells from sale or supply;

j)      Complaints about supplied tissues and cells are examined, the causes of quality defects investigated and appropriate measures taken in respect to prevent the reoccurrence of the quality defects of tissues and cells.

8. The TE must maintain a registry of SOPs, in which every activity (including donation, donor screening, collection, codification, preparation, laboratory testing, storage, transmission and distribution) is clearly defined and described.  It will include aspects related to quality control and quality assurance.  Each of these procedures will be reviewed and monitored regularly and adjusted if necessary.  All revisions are documented, dated and signed for approval.

Keeping records of previous versions should help to ensure that only the most recent version is being used.  Copies of the latest version should be available to the staff of the TE.

9. TEs should take all necessary measures to ensure that the quality system includes at least the following documentation:

a)     Standard operating procedures;

b)    Guidelines;

c)     Training and reference manuals;

d)    Reporting forms;

e)     Donor records;

f)     Information on the final destination of tissues or cells.

This should be described in a Quality Manual.

10. TEs should take all necessary measures to ensure that the documentation is available for inspection by the competent authority or authorities.

11. 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.

12. All the records must be clear and readable, protected from unauthorised amendment and retained and readily retrieved in this condition throughout their specified retention period in compliance with data protection legislation.[3]

13. Donor records required for full traceability must be kept for a minimum of 30 years after clinical use.

A.7.1.3. Non-compliance management

1. 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.

2. 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]

A.7.1.4. Internal Audit

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.[5]

It is recommended that the internal audit plan be created on risk assessment basis.

2. An external audit conducted by a competent person independent of the bank would be desirable.  Both, the findings and corrective actions must be documented.

3. Personnel matters, premises, equipment, documentation, processing, quality control, distribution of the tissues and cells, arrangements for dealing with complaints and recalls, and self-inspection, should be examined at intervals following a pre-arranged programme in order to verify their conformity with the principles of Quality Assurance.[6]

4. Member States shall also ensure that appropriate control measures are in place for the procurement of human tissues and cells.

5. Such inspections and control measures shall be carried out by officials representing the competent authority who shall be empowered to:

a)    Inspect TEs and the facilities of any third parties;

b)    Evaluate and verify the procedures and the activities carried out in TEs and the facilities of third parties that are relevant;

c)     Examine any documents or other records relating to the requirements of this text.

6. The competent authority or authorities shall organise inspections and carry out control measures as appropriate whenever there is any serious adverse reaction or serious adverse event.  In addition, such an inspection shall be organised and control measures shall be carried out at the duly justified request of the competent authority or authorities in another Member State in any such case.

7. Member States shall, upon the request of another Member State or the Commission, provide information on the results of inspections and control measures carried out in relation to the requirements of this text.[7]

8. The use of the checklist tool coming from the EQSTB project is recommended (see G.4. EQSTB CHECKLIST)

A.7.1.5. Product Quality Review/Process Quality Review

1. The tissue establishment should have processes in place for review of the performance of the quality management system to ensure continuous and systematic improvement.[8]

2. Regular periodic quality reviews of all tissues and cells, including export ones, should be conducted with the objective of verifying the consistency of the existing process, the appropriateness of current specifications for both starting materials and finished tissues and cells to highlight any trends and to identify tissues/cells and process improvements.[9]

3. Such reviews should normally be conducted and documented annually; taking into account previous reviews, and should include at least the items indicated in those paragraphs.

4. The results of this review should be evaluated and an assessment should be made whether corrective and preventive action or any revalidation should be undertaken.  Reasons for such corrective actions should be documented.  Agreed corrective and preventive actions should be completed in a timely and effective manner.  There should be management procedures for the ongoing management and review of these actions and the effectiveness of these procedures verified during self-inspection.

5. Quality reviews may be grouped by tissues/cells type, where scientifically justified.[10]

 
A.7.1.5.1. Donor screening

The donor screening process should be evaluated regularly in order to assess its consistency. The Process Quality Review (PQR) will consider whether the procedures are effective.

At least the following issues are suggested to be taken into account:

a)     Previous reviews;

b)    A review of death cases in the common generator centres, number of cases detected in an adequate period of time and cases not detected;

c)     Review of traceability lost cases;

d)    Review of donor contamination or deterioration during maintenance;

e)     Review of familiar and judicial negatives;

f)     Review of non compliance of the consent scope;

g)     Review of donor evaluation and exclusion criteria checklist;

h)    Review of all the critical deviations and non-conformities and their investigations;

i)      Review of any change established in the process;

j)      Review of the key performance indicators.

A.7.1.5.2. Recovery

The recovery process should be evaluated regularly in order to assess its consistency.  This PQR will consider whether the procedures are effective and adequate.

At least the following issues are suggested to be taken into account:

a)     Previous reviews;

b)    Review of facilities and materials microbiological monitoring results;

c)     Review of tissues and/or cells contamination cases caused by operators, materials or facilities;

d)    Review of tissues and/or cells contamination cases caused by the own donor;

e)     Review of cross contamination when applicable;

f)     Review of critical quality controls;

g)     Review of all the critical deviations and non-conformities and their investigations;

h)    Review of any change established in the process;

i)      Review of the process validation studies;

j)      Review of the facilities qualification and equipment calibrations;

k)    Review of the key performance indicators.

A.7.1.5.3. Processing

The processing processes should be evaluated regularly in order to assess their consistency on the obtaining of quality tissues and cells.  This product quality review will consider whether the procedures are effective.

At least the following issues are suggested to be taken into account:

a)     Previous reviews;

b)    Deviations and non-conformities observed during reception activities;

c)     Review of starting materials including packaging materials used in the tissues/cells, especially those from new sources;

d)    Review of critical quality control tests;

e)     Review of all tissues/cells that failed to meet established specification(s) and their investigation;

f)     Review of all significant deviations or non-conformances from the processing procedures, their related investigations, and the effectiveness of resultant corrective and preventive actions taken;

g)     Review of all changes carried out to the processes or analytical methods;

h)    Review of the results of the stability monitoring programme and any adverse trends;

i)      Review of microbial and airborne results of routine monitoring results;

j)      Review of all quality-related returns, complaints and recalls and the investigations performed at the time;

k)    Review of patient follow-up information;

l)      Review of adequacy of any other previous product process or equipment corrective actions;

m)   Calibration and qualification status of relevant equipment and utilities, e.g. HVAC, water, compressed gases, etc.;

n)    Review of the process validation studies;

o)    Review of gowning requirements;

p)    Review of cleanrooms and equipment corrective maintenance activities needed;

q)    Review of any contractual arrangements as defined critical third party agreements section to ensure that they are up to date;

r)     Review of the deviations detected during packaging and labelling operations;

s)     Review of the deviations detected during storage or transport;

t)     Review of the key performance indicators.

9. Quality reviews may be grouped by tissue/cells type where scientifically justified.

 
A.7.1.5.4. Distribution

The distribution processes should be evaluated regularly in order to assess their consistency on maintaining the quality of tissues and cells.  This process quality review will consider whether the procedures are effective.

The following issues are suggested to be taken into account:

a)     Previous reviews;

b)    Deviations and non-conformities observed during shipment activities;

c)     Review of packaging materials used in the tissues/cells, especially those from new sources;

d)    Review of all tissues/cells that suffered any damage during transport because a failure of the shipping system and their investigation;

e)     Review of all significant deviations or non-conformances from the distribution procedures, their related investigations, and the effectiveness of resultant corrective and preventive actions taken;

f)     Review of all changes carried out to the distribution processes;

g)     Review of the shipping system validation studies;

h)    Review of any contractual arrangements as defined in Critical third party agreements section to ensure that they are up to date;

i)      Review of the deviations detected during storage;

j)      Review of the SAE and SAR that might have occurred;

k)    Review of the key performance indicators.

10. Quality reviews may be grouped by tissue / cells type where scientifically justified.

11. It is recommended to extend the quality review to a more general management review including other processes of the organization (e.g. finances, purchasing, personnel, ICT).

A.7.1.6. Recalls

1. There must be personnel authorised within the tissue establishment to assess the need for recall and to initiate and coordinate the necessary actions.

2. 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.

3. Where tissue that has been released is subsequently deemed to have been unsuitable for transplantation, it must be recalled.  Actions must be taken within pre-defined periods of time and must include tracing all relevant tissues.  Any donor who might have contributed to causing a reaction in the recipient must be traced to retrieve available tissues and cells from that donor, as well as to notify hospitals and recipients of tissues and cells, or organs, procured from the same donor in the event that they might have been put at risk.

4. A documented system must be in place for the handling of returned products including criteria for their acceptance into the inventory, if applicable.[11]

5. There should be established written procedures, regularly checked and updated when necessary, in order to organise any recall activity.

6. Recall operations should be capable of being initiated promptly and at any time.

7. All parties to which tissues/cells may have been distributed should be informed promptly if tissues / cells are intended to be recalled because they are, or are suspected of being defective.

8. The distribution records should be readily available in the event of a recall including those for exported tissues/cells.

9. Recalled tissues / cells should be identified and stored separately in a secure area while awaiting a decision on their fate.[12]  If the tissues can not be used for human application after recall, this shall be clearly marked and rejected.However, those tissues can be used for other purposes;

a)     For preparation techniques of some tissues (p.exe control tissue cryopreservation)

b)    For quality control of tissue affected in the tissue bank; it is then included in the record of the rejected tissue;

c)     For medical research.  The donor's consent is required for this specific purpose and the research protocol must be approved by an ethics committee.

11. The progress of the recall process should be recorded and a final report issued, including reconciliation between the delivered and recovered quantities of the tissues/cells.

12. The effectiveness of the arrangements for recalls should be evaluated regularly[13]

A.7.1.7. Complaints and returns

1. There should be written procedures describing the action to be taken, including the need to consider a recall, in the case of a complaint concerning a possible product defect.

2. Any complaint concerning a tissue/cells defect should be recorded with all the original details and thoroughly investigated.

3. If a tissue/cells defect is discovered or suspected, consideration should be given to checking other batches in order to determine whether they are also affected.

4. All the decisions and measures taken as a result of a complaint should be recorded and referenced to the corresponding file.[14]

5. Complaint records should be reviewed regularly for any indication of specific or recurring problems requiring attention and possibly the recall of distributed tissues/cells and to ensure that corrective and preventive actions are implemented and are effective.

6. There should be a written policy that defines the circumstances in which returned tissue might be replaced in the inventory for subsequent re-distribution.  In this case, it should be confirmed that all criteria for quality and safety have been maintained, e.g. temperature control and package integrity.[15]



[1]Directive 2004/23/EC of the European Parliament and of the Council ( Art.16)

 

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

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

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

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

[6] EU Good Manufacturing Practices Guidelines

[7] Directive 2004/23/EC of the European Parliament and of the Council (Art 7)

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

[9] EU Good Manufacturing Practices Guidelines

[10] EU Good Manufacturing Practices Guidelines

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

[12] EU Good Manufacturing Practices Guidelines

[13] EU Good Manufacturing Practices Guidelines

[14] EU Good Manufacturing Practices Guidelines

[15] EU Good Manufacturing Practices Guidelines

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