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First Edition - September 2007Copyright: EQSTB (DG Sanco Project - European Commission)

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Guide for auditing

Tissue Establishments


L i s t o f Au t h o r s :

Theo de By, Bio Implant Services Foundation (The Netherlands)

Clara Fernández, Transplant Services Foundation (Spain)

Aurora Navarro, Hospital Clínic i Provincial de Barcelona (Spain)

Stefan Poniatowski, National Blood Service, Tissue Services Edgware (England)

Esteve Trias, Transplant Services Foundation (Spain)

S p e c i a l T h a n k s t o :

Thomas Bregeon

Scott Brubaker

Rut Carbonell

Deirdre Fehily

Eduardo Fernández Zincke

Martí Manyalich

Amanda Ranson

Caroline Trouet

Nicole van Nierop


1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .72. Regulatory Framework . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .133. Definitions and Abbreviations

3.1. Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .153.2. Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .21

4. Audit Procedure4.1. Outset . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .234.2. Document Submission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .234.3. Audit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .244.4. Post-audit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .244.5. Audit Result . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26

5. Audit ManualPart A: General Policies

A.0 General Considerations for Auditors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .27A.1 Legal and Regulatory Framework . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .27A.2 Standard Operating Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .28A.3 Specific Aspects of the Quality System . . . . . . . . . . . . . . . . . . . . . . . . . . . .30A.4 Data Protection and Anonymity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .31A.5 Traceability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .32A.6 Personnel Training and Qualification . . . . . . . . . . . . . . . . . . . . . . . . . . . . .34A.7 Health and Safety of Staff; Compliance with Legal Requirements . . . . . .36A.8 Packaging and Labelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .38A.9 Records and Registers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .43

Part B: Tissue DonationB.1 Donor Selection and Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .46B.2 Donor Coding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .50B.3 Donor Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .51B.4 Donor Documentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .53

TA BL E O F CO N T E N T S


Part C: Tissue ProcurementC.1 General Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .55C.2 Retrieval Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .56C.3 Retrieval Documentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .59C.4 Transportation to TE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .61

Part D: Tissue ProcessingD.1 General Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .62 D.2 Equipment Suitability, Sterility and Traceability . . . . . . . . . . . . . . . . . . . . .66D.3 Environmental Controls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .68D.4 Traceability of Tissue through Processing . . . . . . . . . . . . . . . . . . . . . . . . .71D.5 Microbiological Testing of Final Tissue . . . . . . . . . . . . . . . . . . . . . . . . . . .72D.6 Adverse Event Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .73

Part E: Tissue StorageE.1 General Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .75E.2 Storage Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .76E.3 Tissue Release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .76

Part F: Tissue DistributionF.1 General Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .78F.2 Transportation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .78F.3 Reception Policies at the End User . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .79F.4 Adverse Event Monitoring and Recall . . . . . . . . . . . . . . . . . . . . . . . . . . . . .78F.5 Waiting Lists and Import/Export Policies . . . . . . . . . . . . . . . . . . . . . . . . . .79

6. Shortcut to Audit Guidance Parts A to F . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .837. Audit Report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .938. Annexes

Annex 1: 2006/86/EC Annex VI, Article 9 . . . . . . . . . . . . . . . . . . . . . . . . . . .104Annex 2: Site Master File . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .105


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1 . I N T RODUC T ION

1.1 Background

This Guide for Auditing Tissue Establishments has been developed as a result of aEuropean project entitled European Quality System for Tissue Banking (EQSTB), a DGSanco project (Directorate General for Health and Consumer Affairs) partiallyfunded by the European Commission and promoted by Hospital Clinic de Barcelona,Spain. It has lasted three years, from May 2004 until May 2007. Fifteen different na-tional organisations and tissue establishments from twelve European countries aretaking part in this project.

The partners of the EQSTB Project are listed below:

Belgian University Tissue Bank (Belgium)Tampere University Tissue Bank (Finland)Agence De La Biomédecine (France)Deutsches Herzzentrum Berlin (Germany)Istituti Ortopedici Rizzoli (Italy)Centro Nazionale Trapianti (Italy)State Forensic Medicine Centre, Department Of Latvian Tissue Bank(Latvia)National Centre For Tissue And Cell Banking (Poland)University Of Medicine And Pharmacy “Victor Babes” Timisoara (Romania)Ruzinov General Hospital Bratislava (Slovakia)Organización Nacional De Trasplantes (Spain)Transplant Services Foundation (Spain)Netherlands Bone Bank Foundation (The Netherlands)Bio Implant Services Foundation (The Netherlands)North London Tissue Bank (United Kingdom)


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i n t r o d u c t i o n

The main objective of this project is to analyse factors that may influence the qualityand safety of the final tissue for transplantation throughout different working areas, inorder to provide greater benefit to recipients. The project aims to develop the method toensure standards of quality and safety in relation to tissue banking activities.

The EQSTB project has been organised into four Working Groups, the objectives ofeach one being focused in a specific area:

1. Standards Working Group: To analyse the different standards or guides used in diffe-rent European tissue establishments (TE) as tissue bank quality and safety systems.Tissue Banks establish protocols which define their activities according to the di f -ferent standards written by various scientific organisations. The analysis focuses onfinding similarities and differences among tissue banks protocols. A study of the rateof implementation of the European Directive in the different participating coun-tries has been performed. Finally, a Guide of Recommendations on tissue bankingstandards and quality and safety key points will be prepared based on the EuropeanDirective.

2. Registry Working Group: To build a Tissue Registry through a multinational Europeannetwork database. Standardised data will be protocolised in order to receive the sameinformation from different tissue banks about donor selection, tissue retrieval, pro-cessing and transplantation. Receiving information about tissue transplantation willguarantee traceability of all the tissues registered. At the same time, adverse reactionsafter tissue transplantation will be registered. Up to now, traceability has not alwaysbeen guaranteed and nor have adverse reactions been recorded.

3. Education Working Group: To design and validate a specialised training model with tis-sue bank personnel which can thereafter become the approved education recom-mended by European Union members. The model will be based on the profile of thetissue bank personnel and the knowledge and training needs detected. The aim will beto use this model as a method of qualifying personnel and validating their knowledgeby providing European Certification.

4. Audit Working Group: To create a European model of Auditing for tissue estab lishments(Audit Guide) based on the results of the other three WGs. This pilot model on au-diting could become a useful tool in implementing the European Directives on Tissuesand Cells (presently Directives 2004/23/EC, 2006/17/EC and 2006/86/EC).

All working groups have contributed to the development of this Audit Guide. WorkingGroup four compiled the information and results obtained from the other working groups,


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including the quality and safety key points detected by WG1, the necessary registry datadefined by WG2 and the pilot training and educational model obtained by WG3. To de-fine the audit model and develop this Audit Guide, WG4 performed a thorough study ofthe European legislation and carried out four pilot audits in participating tissue establish-ments. As a result of all these activities and analyses, the Guide for Auditing TissueEstablishments has been made available.

For a more detailed view of the Sanco-EQSTB project, please visit the website:http://sanco-eqstb.hospitalclinic.org/sanco/index.html.

1.2 Purpose and Application

As recommended by the European Parliament and the Council of the EuropeanUnion, tissue banking activities must be performed in such a way as to ensure the qualityand safety of human tissues and cells. These activities must therefore be consistent withthe requirements set by European Directive 2004/23/EC, and more recently, Directive2006/17/EC, as regards donation, procurement, testing, processing, preservation, storageand distribution of human tissues and cells, and Directive 2006/86/EC as regards trace-ability requirements, notification of serious adverse reactions and events and certain tech-nical requirements for the coding, processing, preservation, storage and distribution ofhuman tissues and cells. The latter establishes that, in order to meet these standards onquality and safety, an audit system is necessary and must be in place for the activities forwhich accreditation, designation, authorisation or licensing is sought.

This Guide for Auditing Tissue Establishments has been produced as a result of the afore-mentioned European project, to put together in a practical and useful way the standardsconsidered to be fundamental for the activities carried out in a TE, and practical guidancefor those individuals who will be auditing tissue establishments. This will guarantee thatthese activities are performed accordingly and in compliance with the requirements of theEuropean Directives. Various experts in tissue banking have collaborated in the develop-ment of this Audit Guide, providing their know-how and giving guidance on how to per-form audits and what to search for.

An audit is a “documented review of procedures, records, personnel functions, equip-ment, materials, facilities, and/or vendors in order to evaluate adherence to written SOPs,standards, and government laws and regulations”.1 During an audit, performance is re-viewed to ensure that those things which should be done in terms of quality managementare being done and documented, and if this is not the case, it provides a framework to

1 Definition from CoE Guide 2004


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allow improvements to be made. This Audit Guide has a standards-based methodology,in which data is collected and performance observed in order to measure current practiceand compare it against those standards. Subsequently, any changes considered necessaryare implemented. This process involves reviewing all the processes carried out in the TE(from donation to distribution of tissues) and assessing the Standard Operating Procedures(SOPs) for compliance with the regulations, and of course to certify that SOPs are actu-ally being adhered to.

Consequently, this Audit Guide aims to:- Provide a useful tool for implementing the requirements of Commission Directives

2004/23/EC, 2006/17/EC and 2006/86/EC- Help auditors comply with the standards on tissue banking activities- Promote diligence and consistency among auditors and audits throughout Europe

Audits may be performed in different ways. These can be carried out as self-assess-ment, internally by the TE’s own trained quality personnel, by independent bodies organ-ising a peer audit and/or to third parties. Thus, the potential uses of audits are:

- Self-assessment: a method of the TE’s own personnel to review each step in a processin which they are involved in order to ensure ongoing improvement.

- Internal audits: organised by the quality personnel of the TE in order to assess com-pliance to standards and procedures.

- External peer audits: carried out by independent bodies, often designated ap-proved/competent authorities, which are generally required for accreditation and li-censing purposes

- Third party audits: performed by the TE’s quality personnel to verify that the thirdparty that is providing a service or product is performing its activity according to thesigned contract.

It is recommended that an attitude exists within the TE to promote the open report-ing of errors and incidents and hence encourage the subsequent improvements in prac-tice that investigations of such events can bring.

1.3 Structure, Contents and Approach

As can be seen in the table of contents, this Guide for Auditing Tissue Establishmentsis divided into eight sections:

Section 1: IntroductionSection 2: Regulatory FrameworkSection 3: Definitions and Abbreviations


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Section 4: Audit ProcedureSection 5: Audit ManualSection 6: Shortcut to Audit Guidance of all PartsSection 7: Audit ReportSection 8: Annexes

The Audit Manual (Section 5) is structured according to each main tissuebanking activity (parts A to F), which are themselves subdivided into differenttopics. For each topic, the standard is specified, followed by guidance for auditors(which includes explanations and examples), and finally by a set checklist questionspertaining to that standard. These standards, or quality and safety core require-ments, are mainly built upon the requirements of the EU Directives, but also,they take into account suggestions from tissue banking experts as well as rec-ommendations from the European Association of Tissue Banks (EATB). Pleasesee the Regulatory Framework section (Section 2) for further information onwhat this guide is based on.

Part A of the Audit Guide relates to General Policies for TEs, which include generalconsiderations for auditors prior to the audit and the general policies for tissue establish-ments. These include the legal and regulatory framework, SOPs, specific aspects of thequality system and issues relating to data protection and anonymity, traceability, personneltraining and qualification, health and safety of staff, packaging and labelling, and recordsand registers.

Part B deals with Tissue Donation, itself subdivided into four items. These are donor se-lection and evaluation, donor coding, donor testing and donor documentation.

Part C covers Tissue Procurement, which encompasses general principles (such as con-sent, identification and coding), the conditions for retrieval, procurement documentationand transportation to TE.

Part D, which concerns Tissue Processing, is subdivided into six items: general principles(such as reception policies, identification, validation, pooling, etc.), equipment suitability,sterility and traceability, environmental conditions, traceability, microbiological testing offinal tissue and adverse event management.

Part E deals with Tissue Storage, which comprises a couple of general principles(validation and quarantine), storage conditions and issues associated with tissue re-lease.


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Finally, part F refers to Tissue Distribution. In this part, the following factors are ex-plored: general principles, issues related to transport, reception policies at the end user, reg-ister of recipients, adverse event/reaction monitoring and recall, waiting lists andimport/export policies.

This Audit Guide is meant for auditing TE against the current EU Directives, and itis intended for two different groups of individuals:

1. For auditorsIt will be very helpful for auditors to guide them through an audit, since it contains allthe standards, or quality and safety key requirements, related to tissue banking, guid-ance on what to search for and review while auditing, and a checklist consisting of aset of questions relating to each standard with writing space for the auditor to notedown any observations and comments associated with specific items.

2. For tissue establishmentsIt can be used by TEs to give them an idea of what is expected of them and what au-ditors will be looking for. The checklist with the sets of questions can be utilised as aself-assessment tool so that the TE can “audit” itself.

The checklist mentioned above will be very useful for tissue establishments to auditthemselves and verify their compliance to EU Directives. For auditors, what will very help-ful and practical are the standards and the guidance; the checklist can be used as an ‘aide-memoire’ at certain stages during the audit (or at its end) whenever the auditor wants togo into more detail for a specific key point.

It is important to keep in mind that auditing is an essential quality management tooland should be conducted in an objective and independent way by designated, trained andcompetent persons.


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2 . R EGU L ATORY F R A ME WOR K

As mentioned in the introduction, this Guide has been developed to create amodel for tissue banking auditing so as to provide the means for implementing therequirements of the current European Directives, which are that tissue banking ac-tivities be performed in a way that ensures the safety and quality of tissues and cells.Hence, this guide is derived from and takes into account the requirements and reg-ulations of:

· Commission Directive 2004/23/ECof the European Parliament and of the Council setting standards of quality and safetyfor the donation, procurement, testing, processing, preservation, storage and distri-bution of human tissues and cells- adopted by Parliament and Council on March 31, 2004- transposed in all Member States by April 7, 2006

· Commission Directive 2006/17/ECimplementing Directive 2004/23/EC as regards certain technical requirements forthe donation, procurement and testing of human tissues and cells- adopted by the Commission on February 8, 2006- transposed in all Member States by November 1, 2006

· Commission Directive 2006/86/ECimplementing Directive 2004/23/EC as regards certain technical requirements con-cerning traceability and notification of serious adverse reactions and events and cer-tain technical requirements for the coding, processing, preservation, storage anddistribution of human tissues and cells- adopted by the Commission on October 24, 2006- transposed in all Member States by September 1, 2007


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r e g u l a t o r y f r a m e w o r k

The European Directives can be found in .pdf format on the European Commissionwebsite, in diverse languages:

http://ec.europa.eu/health/ph_threats/human_substance/legal_tissues_cells_en.htmIn addition to the requirements stated above, this Audit Guide also bears in mind the

recommendations from:

· European Association of Tissue Banks (EATB): Common standards for tissueand cell bankingIn 2003, this association published common standards to ensure that tissue and cellbanking conduct meets acceptable norms of technical and ethical performance inprocurement, processing, preservation and distribution of human tissues and cells fortransplant, as well as screening, labelling, storage, donor selection criteria, testing andrecord keeping. EATB also carries out programs for training, accreditation and certi-fication of tissue bank personnel to guarantee that all the activities are performed ina professional manner. These standards apply to human tissues and cells used for ther-apeutic purposes, excluding reproductive and genetically modified tissues. It is stronglyrecommended that these standards be used as a reference and guideline. These can beacquired through the EATB website, which is: www.eatb.de.

· Tissue banking professionals throughout EuropeThis Guide provides as well recommendations from European tissue banking expertswho have produced it. These recommendations, in some cases, are more stringentthan the EU Directives. (Where applicable, recommendations are differentiated fromactual requirements).

Thus, this Guide is not only the means to verify compliance with the minimum re-quirements of the European Directives, but also to keep in mind other recommendationsthat will enhance the performance in the TE and hence the level of quality and safety oftissues and cells.


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3 . DEF I N I T IONS A NDA BBR E V I AT IONS

3.1 DEFINITIONS

· Allocation criteria: a set of criteria to ensure that recipients get equitable access tohealthcare of appropriate quality for all, in which potential recipients get a rankingorder on the basis of relevant medical urgency criteria (including waiting time).

· Allogeneic use: cells or tissues removed from one person and applied to another(2004/23/EC).

· Aseptic processing: processing is performed under clean room conditions. No ter-minal sterilisation that sterilises all product or package components is carried out(EATB 2003).

· Audit: a documented review of procedures, records, personnel functions, equipment,materials, facilities and/or vendors in order to evaluate adherence to written SOPs,standards or government laws and regulations (CoE Guide 2004).

· Autologous use: cells or tissues removed from and applied to the same person(2004/23/EC).

· Batch (see also Lot): a defined quantity of tissue produced according to a single pro-cessing cycle during the same processing cycle which is intended to have uniform char-acter and quality within specific limits, precluding mixing of cells and/or tissue fromtwo or more donors (EATB 2003).

· Bioburden: population of viable micro-organisms found on a given amount of ma-terial (EATB 2003).

· Calibration: the set of operations which establish, under specified conditions, the re-lationship between values indicated by a measuring instrument or measuring system,or values represented by a material measure, and the corresponding known values ofa reference standard (EUDRALEX Volume 4 - Medicinal Products for Human andVeterinary Use: Good Manufacturing Practice).


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d e f i n i t i o n s a n d a b b r e v i a t i o n s

· Cells: individual human cells or a collection of human cells when not bound by anyform of connective tissue (2004/23/EC).

· Clean, non sterile: use of methods and techniques that keep microbial contaminationof the tissues collected at a minimum level (EATB 2003).

· Clean-room technology: as all the technical and procedural actions required to controlmicrobial and particulate contamination in work areas, and maintain predetermined lev-els of contamination (EATB 2003).

· Competency: the ability of an employee to acceptably perform tasks for which he/shehas been trained (AATB Standards 11th edition).

· Complaint: any written or oral communication concerning dissatisfaction with the iden-tity, quality, packaging, durability, reliability, safety, effectiveness, or performance of cellsand/or tissue (AATB Standards 11th edition).

· Cost: the actual costs for retrieval, processing, preservation, storage, distribution, edu-cation, research and development (EATB 2003).

· Critical: means potentially having an effect on the quality and/or safety of having con-tact with the cells and tissues (2006/86/EC). Having an effect on fundamental require-ments for quality and safety, thus (potentially) endangering the safety of recipients orpersonnel of the TE.

· Demineralised bone: implant made from osseous tissue with a measurable residualbelow 5 % in its calcified intercellular calcium substances (Standards of Tissue Banking,American Association of Tissue Banks, 1990).

· Direct use: any procedure where cells are donated and used without any processing andbanking (2006/17/EC).

· Disinfection: a process reducing the number of viable microorganisms, but does notinsure the complete destruction of microbial forms, such as spores and viruses (EATB2003).

· Distribution: transportation and delivery of tissues or cells intended for human appli-cations (2004/23/EC).

· Donation: donating human tissues or cells intended for human applications(2004/23/EC).

· Donor: every human source, whether living or deceased, of human cells or tissues(2004/23/EC).

· Donor: live donor: any donor who has not undergone brain death (EATB 2003).· Donor: deceased donor: any donor who has undergone brain death or cardiac death

(EATB 2003).· Donor of surgical residues: any donor where organs, tissues or cells are collected dur-

ing a surgical procedure where the material is removed for therapeutic purposes otherthan to obtain organs, tissues, or cells (CoE Guide 2004).

· Dura mater: a type of soft tissue that includes the pachymeninx (thick, membranous)tissue covering the brain (AATB Standards 11th edition).


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· End user: facility, or medical practitioner who performs transplantation procedure(EATB 2003).

· Error: a departure, whether intentional or not, from the SOPM, standards, or applica-ble federal, state, and/or local laws and/or regulations during donor screening, testing,retrieval, processing, quarantine, labelling, storage, distribution, or dispensing of cellsand/or tissues which may cause infectious disease transmission, adversely affect the clin-ical performance of cells and/or tissue, and/or interfere with the ability to trace cellsand/or tissue to the donor (AATB Standards 11th edition).

· Exceptional release: the dispensing of a unit of cells and/or tissue, because of an un-usual clinical need, which circumvents normal release procedures. This requires writtenapproval from both the Medical Director and the transplanting physician (AATBStandards 11th edition).

· Expiry date: the date after which tissues or cells are no longer suitable for use (CSA2003).

· Facility: any area used in the procurement, processing, testing, storage or distributionof tissues/cells (CoE Guide 2004).

· Finished tissue: cells and/or tissue that have been fully processed, enclosed in its finalcontainer, labelled and released to distribution inventory (AATB Standards 11th edition).

· Freeze-dried tissue (synonym: lyophilised): achieved by freezing tissue in such a waythat water is converted into ice in situ and subjected thereafter to a vacuum sufficient tofacilitate sublimation of the ice thus formed (CoE Guide 2004).

· Good Manufacturing Practice (GMP): a quality assurance scheme, which ensures thatmedicinal products are consistently produced and controlled to quality standards (UK HTACode of Practice Draft, 2006).

· Graft transplant material: the result of a series of operations including collection, pro-cessing, testing and package, ready to be delivered and used by the medical practitioner(CoE Guide 2004).

· Harm: physical injury and/or damage to health and property (ISO/CD 14971 MedicalDevices and Risk Management - Application of Risk Management to Medical Devices.)

· Hazard: potential source of harm. (ISO/CD 14971 Medical Devices and RiskManagement - Application of Risk Management to Medical Devices).

· Human application: the use of tissues or cells on or in a human recipient and extra-corporal applications (2004/23/EC).

· Informed consent: a procedure whereby information concerning the donationprocess is presented to the donor or donor’s next of kin with an opportunity forthem to ask questions, after which specific approval is documented (AATB Standards11th edition).

· Label: a display of written, printed or graphic matter upon the immediate container ofany article (US Food and Drug Administration (FDA) Guidance Document The Federal Food,Drug and Cosmetic (FD&C) Act, Section 201 (k)).


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· Lot (see also Batch): cells and/or tissue produced from one donor at one time usingone set of instruments and supplies. Also refers to a quantity of reagents, supplies, orcontainers that is processed or manufactured at one time and identified by a unique iden-tification number recipient.

· Major non-conformity: if it poses a potential or indirect threat to the safety of a donor,recipient or staff member.

· Medical clinician: person licensed by a country to practice the healing arts within itsjurisdiction (EATB 2003).

· Minor non-conformity: if it poses a minimal but not significant risk.· Next of kin: the person(s) most closely related to a deceased individual as designated by

applicable law such as the Uniform Anatomical Gift Act (AATB Standards 11th edition).· Non-conformity: non compliance with the specified requirements (EATB 2003).· Organ: a differentiated and vital part of the human body, formed by different tissues,

which maintains its structure, vascularisation and capacity to develop physiological func-tions with a significant level of autonomy (2004/23/EC).

· Organisations responsible for human application: a health care establishment or aunit of a hospital or another body which carries out human application of human tis-sues and cells (2006/86/EC).

· Partner donation: the donation of reproductive cells between a man and a woman whodeclare that they have an intimate physical relationship (2006/86/EC).

· Pooling: the physical contact or mixing of cells or tissues from two or more donors ina single container (CoE Guide 2004).

· Preservation: the use of chemical agents, alterations in environmental conditions orother means during processing to prevent or retard biological or physical deteriorationof cells or tissues (2004/23/EC).

· Procedure: a series of technical steps precisely followed in a defined order (EATB 2003).· Processing: all operations involved in the preparation, manipulation, preservation and

packaging of tissues or cells intended for human applications (2004/23/EC).· Procurement: a process by which tissue or cells are made available (2004/23/EC).· Procurement organisation: a health care establishment or a unit of a hospital or another

body which undertakes the procurement of human tissues and cells and which may not beaccredited, designated, authorised or licensed as a tissue establishment (2006/86/EC).

· Product recall: to request from distribution any product which may be related to an ad-verse event or reaction. The request to return a tissue or batch to a tissue establishmentdue to the discovery of a safety issue.

· Quality: the conformance of a tissue or process with pre-established specifications orStandards (AATB Definitions 2000).

· Quality assurance: all those planned and systematic actions necessary to provide ade-quate confidence that a product or service will satisfy given requirements for quality(CoE Guide 2004).


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· Quality control: the operational techniques and activities that are used to fulfil require-ments for quality (EATB 2003).

· Quality control: specific tests defined by the Quality Assurance Program to be per-formed in order to monitor retrieval, processing, preservation and storage, tissue qual-ity and test accuracy. These may include but are not limited to: performance evaluation,testing and controls used to determine the accuracy and reliability of the tissue bank’sequipment and operational procedures as well as the monitoring of supplies, reagents,equipment and facilities (AATB Definitions, 2000).

· Quality management: the coordinated activities to direct and control an organisationwith regard to quality (2006/86/EC).

· Quality system: the organisational structure, defined responsibilities, procedures,processes and resources for implementing quality management; includes all activitieswhich contribute to quality, directly or indirectly (2006/86/EC).

· Quarantine: the status of retrieved tissue or cells, or tissue isolated physically or byother effective means, whilst awaiting a decision on their acceptance or rejection(2004/23/EC).

· Recall: an action taken by a tissue bank to locate and retrieve cells and/or tissue fromdistribution and dispensary inventories (AATB Standards 11th edition).

· Recipient: the person into whom an organ, tissue or cells is/are grafted/implanted (CoEGuide 2004).

· Reimbursement: a payment of money equal to, but not exceeding, expenses necessar-ily incurred (EATB 2003).

· Reproductive cells: all tissues and cells intended to be used for the purpose of assistedreproduction (2006/86/EC).

· Residual moisture: the ratio of the mass of residual water to the mass of lyophilizate(EATB 2003).

· Residual water: content is less than 6 % by gravimetric analysis (CoE Guide 2004).· Responsible person: a person who is authorized to perform designated functions for

which he or she is trained and qualified (AATB Standards 11th edition).· Retrieval: the procurement, harvesting or collection of transplantable tissues or cells,

whether viable or not, from a living or non-living donor, for the benefit of one or morepatients (EATB 2003).

· Risk: the probability of a hazard causing harm and the degree of severity of the harm(ISO/CD 14971 Medical Devices and Risk Management - Application of Risk Management toMedical Devices).

· Risk analysis: investigation of available information to identify hazards and estimate risk(ISO/CD 14971 Medical Devices and Risk Management - Application of Risk Management toMedical Devices).

· Safety: freedom from unacceptable risk of harm (ISO/CD 14971 Medical Devices andRisk Management - Application of Risk Management to Medical Devices).


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· Serious adverse event: any untoward occurrence associated with the procurement, test-ing, processing, storage and distribution of tissues and cells that might lead to the trans-mission of a communicable disease, to death or life-threatening, disabling orincapacitating conditions for patients or which might result in, or prolong, hospitalisa-tion or morbidity (2004/23/EC).

· Serious adverse reaction: an unintended response, including a communicable disease,in the donor or in the recipient, associated with the procurement or human applicationof tissues and cells, which is fatal, life-threatening, disabling, incapacitating or which re-sults in, or prolongs, hospitalisation or morbidity (2004/23/EC).

· Standards: specifications, requirements and procedures applicable to donor screening,tissue procurement, testing, processing, storage and distribution designed to ensure thecontinued purity, potency, clinical efficacy and safety of such tissues during the dating pe-riod (EATB 2003).

· Standard Operating Procedures (SOPs): written instructions describing the steps ina specific process, including the materials and methods to be used and the expected endproduct (2006/86/EC).

· Sterilisation: a validated physical or chemical process to destroy, inactivate or reduce mi-croorganisms to a sterility assurance level of 10-6 (CoE Guide 2004).

· Storage: maintaining the product under appropriate controlled conditions until distri-bution (2004/23/EC).

· Surgical residues: collection of tissues/cells during a surgical procedure where the ma-terial is removed for therapeutic purposes other than to obtain organs, tissues, or cells(CoE Guide 2004).

· Terminal sterilisation: a validated process whereby tissue is sterilized within its pri-mary packaging (AATB Standards 11th edition).

· Tissue: all constituent parts of the human body formed by cells (2004/23/EC). Humantissue includes all constituted parts of a human body formed by cells including surgicalresidues and amnion, but excluding organs, blood and blood products. New products en-gineered from human tissue are included (EATB 2003).

· Tissue container: wrapping system insuring the integrity and sterility of tissues (CoEGuide 2004).

· Tissue establishment (TE): a tissue bank or a unit of a hospital or another body whereactivities of processing, preservation, storage or distribution of human tissues and cellsare undertaken. It may also be responsible for procurement or testing of tissues andcells (2004/23/EC).

· Tissue package: additional wrapping used to protect one or more tissue containersduring transit (EATB 2003).

· Traceability: the ability to locate and identify the tissue/cell during any step from pro-curement, through processing, testing and storage, to distribution to the recipient or dis-posal, which also implies the ability to identify the donor and the tissue establishment or


21


the manufacturing facility receiving, processing or storing the tissue/cells, and the abil-ity to identify the recipient(s) at the medical facility/facilities applying the tissue/cells tothe recipient(s); traceability also covers the ability to locate and identify all relevant datarelating to products and materials coming into contact with those tissues/cells(2006/86/EC).

· Validation (or ‘qualification’ in the case of equipment or environments): establishingdocumented evidence that provides a high degree of assurance that a specific process,piece of equipment or environment will consistently produce a product meeting its pre-determined specifications and quality attributes; a process is validated to evaluate theperformance of a system with regard to its effectiveness based on intended use(2006/86/EC).

3.2 ABBREVIATIONS

CNS: Central Nervous SystemEATB: European Association of Tissue BanksEU: European UnionGMP: Good Manufacturing PracticesHBs-Ag: Hepatitis B Virus surface AntigenHCV-Ab: Hepatitis C Virus AntibodiesHIV: Human Immunodeficiency VirusMS: Member StatesN/A: not applicablePPE: Personal Protective EquipmentSAR/E: Serious Adverse Reaction / EventSOPs: Standard Operating ProceduresTE: Tissue EstablishmentTPHA: Treponema pallidum Haemaglutination Assay



23

4 . AUDI T PRO CEDUR E The audit methodology of this guide is determined by an evaluation of the docu-

mentation provided by the applicant TE and by the on-site audit.

The audit methodology should consist of the following steps:

4.1 OUTSET

The audit lead assessor should announce to the auditees that an audit is going to takeplace, and propose a date or timeframe for it. The purpose of the audit also needs to bestated (for instance for the EU, on behalf of the national inspector, a second party, etc.The lead assessor will indicate who the auditors are, and must give a short explanation ofthe procedure and the personnel who are expected to attend (quality management, direc-tor and/or others).

4.2 SUBMISSION OF DOCUMENTS

The applicant centre should submit the pre-audit documentation approximately 3weeks prior to the expected audit date. This way, the appointed auditors will have enoughtime to review the files.

The documentation to be submitted should be:· Site Master File duly completed (see Annex 2), including:

- Identification of key individuals and their responsibilities- Premises, equipment, etc.- Tissue activities: tissues procured, processed and supplied and level of activity- Description of the quality system in operation- Organisational chart- Site plan

· Quality Manual (including list of SOPs), where possible


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a u d i t p r o c e d u r e

4.3. AUDIT

The audit will be arranged between the auditors and the applicant centre. The timenecessary for the on-site audit is decided in advance by all involved. Depending on the sizeof the tissue establishment and the level of activity, 2 or 3 days might be appropriate. Theaudit is performed by persons qualified by training and experience in tissue banking ac-tivities, who have adequate technical training and expertise as auditors, and have knowl-edge of the European Directives. It is fundamental that an independent and objectiveattitude is maintained by the auditors and the planning and performance of the audit is car-ried out professionally. The auditors are chosen in such a way as to guarantee that theteam has the required knowledge and experience to adequately examine the applicant pro-gramme. If any conflict of interest is perceived, applicants are entitled to call for a changein auditors prior to the audit.

The on-site audit focuses on a series of standards on tissue banking; in this guide,these standards (or quality and safety core requirements) are provided, together withpractical guidance on auditing. This methodology is effective in focusing the con-tent of the audit on the defined core requirements regarding tissue donation, pro-curement, processing, storage and distribution, as required by the EuropeanDirectives.

Auditor profile:The team of auditors should ideally be composed of three experts with expertise in

the following areas:

- Expert I: quality knowledge. ISO and GMP training- Expert II: health organisation background- Expert III: technical processes

All auditors should have experience and training in auditing. In some cases, depend-ing on the country, it might be necessary to have an interpreter with the team to verify doc-umentation and facilitate the entire process.

4.4. POST-AUDIT

Following the audit, the team makes up the audit report based on its own observations,and taking into account those of other auditors if applicable. This report will state whetherthe tissue banking activities are carried out in accordance with the requirements of theDirective. The team will review and agree on findings and will classify any non-conform -ities that might appear.


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An Audit Report form is available in Section 7 of this Guide (page 91). This report isstructured as follows:

- Date, TE data and name and responsibilities of auditees and auditors- Objectives and scope of the audit- List of all the areas/parts that comprise tissue banking- Critical, major and minor non-conformities- Observations- Audit summary and strong points- Timeline for corrective actions- Signature of auditors

In the list of parts audited, auditors should tick the areas audited and the non-con-formities that have appeared.

A verbal report on findings will be provided to key staff members of the tissueestablishment at the end of the audit. The written Audit Report should be sent to theTE within two weeks, and it will lay out the non-conformities and provide a timescaleof corrective actions (by which the non-conformities should be corrected) so thatproper audit closure can occur in a timely fashion. For EU Directive requirements,it will be necessary to achieve 100% of the standard conditions; however, in someother areas, a lower percentage might still be considered acceptable (non-adherenceto recommendations and voluntary standards will not be subject to non-conformityjudgement).

Facilities are given a reasonable period of time to correct the noted non-conformities.It is important to reach agreement about the recommendations for change and improve-ment. The facility should come up with a corrective action plan stating who is named re-sponsible for each amendment and the timescale for its completion.

The classification of the non-conformities will be based on the following system:

- “CRITICAL non-conformity” if it poses an immediate and serious threat to thesafety of a donor, recipient or staff member

- “MAJOR non-conformity” if it poses a potential or indirect threat to the safetyof a donor, recipient or staff member

- “MINOR non-conformity” if it poses a minimal but not significant risk.

Any other observations which are not considered to be non-conformities but the au-ditors think should be noted to the TE, should also be set out in the Audit Report.


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4.5. AUDIT RESULT

After drawing up the Audit Report and giving the TE some time to correct the non-conformities, the auditors should request “evidence” to show that the changes and im-provements have been made. This evidence shall be submitted to the audit team to confirmthat the TE now meets the requirements of the standards.

However, depending on the number and severity of the non-conformities noted, re-consideration of the additional documentation may be required and/or a decisive on-sitere-audit may be regarded as necessary.

This stage is critical as it shows whether the outcome of the audit process has beencompleted. The results of the good audit should be disseminated locally and, where pos-sible, nationally (for example via professional journals and transplant organisations).


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5 . AUDI T M A N UA L

PART A: GENERAL POLICIES

A.0. GENERAL CONSIDERATIONS FOR AUDITORS

1. Communicate with establishment to be audited ahead of time about: agenda, iden-tity of auditor(s), procedure and estimated duration of the audit.

2. Request the duly completed TE’s Site Master File (see Annex 2) some days beforethe audit.

3. Explain the nature and the scope of the audit in writing.4. Arrange confidentiality of the auditors.5. Ask for certificates and/or copies of audit reports from other auditors.6. Communicate with each other to prepare the audit some days before travelling to

the institution to be audited.

A.1 LEGAL AND REGULATORY FRAMEWORK

STANDARD: The TE must be aware of its legal framework. EU Directives must be re-

ferred to and be present. Relevant guidelines or regulations (EATB, EEBA, na-tional peer organisations’ guidelines) should be referred to and be present.

The TE must have a clear organisational structure with clinical and qualitysystem responsibilities defined, as well as the quality system clearly described.

AUDIT GUIDANCE: Check presence of copies of the European Directives and the applicable

law(s).Review the organisational chart and Quality System manual, and look for ref-

erences to laws and regulations.


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a u d i t m a n u a l

CHECKLIST: Legal and Regulatory Framework

Does the TE keep copies of the laws, regulations and/or guidelines it follows?Yes No N/A

Does the TE have an established clear organisational structure? Yes No N/A Are clinical and quality system responsibilities defined? Yes No N/A Is the Quality System clearly described? Yes No N/A Auditor comments: _______________________________________________________________________________________________________________________________________________________________________________________________

A.2 STANDARD OPERATING PROCEDURES (SOPs)

STANDARD: TE must have a set of authorised Standard Operating Procedures (SOPs) which

define responsibilities and describe how procedures should be carried out and bywhom. These SOPs must comply with the requirements of the Directive. For everycritical activity, the material, equipment and personnel involved must be identifiedand documented. All personnel in the TE must follow the SOPs detailed in the man-ual. There must be a document control procedure in place to ensure that only cur-rent versions are in use, and any changes done in the SOPs must be reviewed, dated,approved, documented and implemented by authorised personnel. The SOP manualshould where relevant include, but not be limited, to the following:

- Standard procedures for donor screening/eligibility, consent, retrieval,processing, preservation, packaging, labelling, testing, storage, release andtransportation/distribution or disposal.

- Policies for quality assurance and quality control.- Laboratory procedures for tests performed. - Specifications for materials used including supply, reagents, storage media,

packaging materials.- Procedures for personnel and facility safety.- Standard procedures for facilities maintenance, cleaning and waste disposal

procedures.- Methods for verification of the effectiveness of sterilisation procedures.- Procedures for equipment maintenance, calibration and validation.- Environmental and microbiological conditions, and the methods used

for controlling, testing and verification.- Physiological and physical test specifications for materials.- Methods for determination of shelf life, storage temperature and assigning

expiry dates of tissues and cells.


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- Determination of inserts and/or label text.- Policies and procedures for release of tissue for transplantation.- Procedures for adverse events reporting and corrective actions.- Policies and procedures for donor/recipient tracking and product

recall.

AUDIT GUIDANCE:The TE must provide the audit team with a table of contents of the SOP

Manual, since there will not be time to read the entire manual during the on-siteaudit. This table of contents should be examined for evidence of SOPs address-ing each item (listed above) before arriving at the audit site. Select one SOP atrandom and verify that the material, equipment and personnel involved are iden-tified. Review the document control procedure. Verify that only the current ver-sion of the SOP is in use.

CHECKLIST: SOPs

Is there a set of authorised Standard Operating Procedures (SOPs) which define the re-sponsibilities? Yes No N/A Do they describe how procedures should be carried out and by whom? Yes No N/A Where relevant, do the SOPs include, but are not limited, to the following?

- Standard procedures for donor screening/eligibility, consent, retrieval, processing, preservation,packaging, labelling, testing, storage, release and transportation/distribution or disposal.

Yes No N/A - Quality Assurance and quality control policies. Yes No N/A - Laboratory procedures for tests performed. Yes No N/A - Specifications for materials used including supply, reagents, storage media, packaging materials.

Yes No N/A - Personnel and facility safety procedures. Yes No N/A - Standard procedures for facilities maintenance, cleaning and waste disposal procedures.

Yes No N/A - Methods for verification of the effectiveness of sterilisation procedures. Yes No N/A - Equipment maintenance, calibration and validation procedures. Yes No N/A - Environmental and microbiological conditions, and the methods used for controlling, testing

and verification. Yes No N/A - Physiological and physical test specifications for materials. Yes No N/A - Methods for determination of shelf life, storage temperature and assigning expiry dates of tis-

sues and cells. Yes No N/A - Determination of inserts and/or label text. Yes No N/A - Policies and procedures for release of tissue for transplantation. Yes No N/A


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- Procedures for adverse events reporting and corrective actions. Yes No N/A - Donor/recipient tracking and product recall policies/procedures. Yes No N/A

Auditor Comments: ________________________________________________________________________________________________________________________________________

A.3 SPECIFIC ASPECTS OF THE QUALITY SYSTEM

STANDARD: The Quality System:- Must be based on principles of good practice.- Must comply with the European Directive requirements.- Must comply with national and local legislation requirements.- Should take into account the EATB standards and the GMP requirements

which apply to tissue banking.- Must have a set of authorised SOPs, guidelines, training and reference man-

uals, reporting forms, donor records and information on the final distribution oftissues and cells.

- Must ensure that work performed is standardised and that all steps are trace-able.

- Must have written agreements with third contracted parties (applying par-ticularly where a key step of the process (e.g. donor history, procurement, sterili-sation, transport) is carried out by another organisation).

Quality Review Requirements:- There must be an audit system in place for those activities for which ac-

creditation, designation, authorisation or licensing is required. Competent andtrained persons must perform an independent audit at least every 2 years, inorder to verify compliance with the approved protocols and the regulatory re-quirements.

- If there are deviations from the required standards of quality and safety,there must be documented investigations, including any corrective and preven-tive actions (to be documented and assessed for effectiveness after implementa-tion), and notification of serious adverse events and reactions (SAE/R).

- TE should have processes in place for review of the performance of thequality management system to ensure continuous and systematic improvement.

AUDIT GUIDANCE:Ask the responsible person to show you the Quality System manual, the list

of SOPs (and one random procedure), training manuals, a donor record, written


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agreements between TE and contracted parties, internal and external auditing sys-tem in place, system for detecting non-conformities, notifying SAE/Rs and proofof preventive/corrective actions.

CHECKLIST: Specific Aspects of the Quality System

1. Quality SystemDoes the Quality System:

- Comply with the European Directive requirements? Yes No N/A - Comply with the national legislation requirements? Yes No N/A - Take into consideration:

EATB standards Yes No N/A GMP requirements applying to tissue banking Yes No N/A

- Have a set of authorised SOPs? Yes No N/A - Ensure that work performed is standardised and all steps are traceable?

Yes No N/A - Have written agreements with third contracted parties (applying particularly where a

key step of the process is carried out by another organisation)? Yes No N/A

2. Quality ReviewIs there an audit system in place for the activities for which accreditation (or other) is re-quired? Yes No N/A Do trained and competent persons perform the audit independently?

Yes No N/A If there are deviations from the required standards of quality and safety, are there docu-mented investigations, including corrective and preventive actions?

Yes No N/A Does the TE have processes in place for review of the performance of the quality man-agement system? Yes No N/A Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________

A.4 DATA PROTECTION AND ANONYMITY

STANDARD: The applicable law must be present, or link should be given in the relevant

SOPs. Procedures shall correspond with 95/46/EC (1995) and with any addi-tional national regulations. All data available to third parties must be renderedanonymous so that neither donors nor recipients remain identifiable. Unauthorised


32


disclosure of information must not occur, whilst guaranteeing traceability of do-nations. Data security measures shall be in place as well as protections againsttransfer of information and data modifications in donor records and deferralrecords. There must be procedures in place to sort out data inconsistencies. Policymust be demonstrated at a practical level. The identity of the recipient must notbe revealed to the donor or his/her family, and vice versa. Passwords must becontrolled. There must be a system for the management of password renewal.

AUDIT GUIDANCE:Verify that donor and recipient information remains unidentifiable in data

available to third parties. Check that unauthorised personnel do not have accessto any information that requires it. Check for password renewal management.Beware of uncontrolled passwords on PCs, on post-its, etc.

CHECKLIST: Data Protection and Anonymity

Is the law and other regulations/guidelines applied present and in SOPs?Yes No N/A

Do procedures correspond with 95/46/EC and with any additional national regulations?Yes No N/A

Is there a system for the control of passwords in place? Yes No N/A Is there a system for the management of password renewal in place? Yes No N/A Is donor and recipient data to which third parties have access rendered anonymous?

Yes No N/A Is the identity of the recipient revealed to the donor or his/her family, or vice versa?

Yes No N/A Is there a procedure in place for the resolution of data inconsistencies?

Yes No N/A Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________

A.5 TRACEABILITY

STANDARD: An effective and accurate system must be defined to ensure unique iden-

tification of tissues and cells throughout the entire banking process, fromreceipt to distribution. A system of vigilance and a procedure for recall andadverse events/reactions shall be available for review. It is recommended thatthe end user provides the TE with a follow-up form on the reception and


33


transplantation of tissues to ensure full traceability. The TE must know thedate of distribution or disposal, and the identification of the clinician or end-user facility. It is recommended that the TE also receive information onwhere, when and by whose order the transplant was distributed. Data re-quired for full traceability must be kept for a minimum of 30 years after clin-ical use.

This procedure should at least contain the process to trace data:- From the tissue to the full donor records, including medical and be-

havioural history, testing, procurement and release.- Throughout the processing and storage process (including identifica-

tion of equipment and reagents used) (detailed in “Processing andStorage” section).

- From the recipient to the donor-(tissue).- From the tissue at risk to all other distributed tissues from the same

donor, and/or the same batch; the names of the medical facilities andthe recipients should be available.

Traceability must be supported by adequate labelling, and should be sup-ported by adequate computer systems.

Assurance of traceability: see Annex VI of Directive 2006/86/EC1 forInformation on the minimum donor/recipient data set to be kept by TEsand organisations responsible for human application (see Annex 1).

AUDIT GUIDANCE:Review adverse event and recall procedures (see section F.6).Review four donor records at random and verify that traceability is en-

sured. For computer systems, perform a trial: check how tissue allocation isperformed and what the criteria are. Select one finished released tissue atrandom and ask staff to show you how they can find the associated donorrecord, which lots and batches of reagents were used in the processing, whereit is documented that the tissue was released for distribution and by whom,etc.

CHECKLIST: Traceability

Is there an effective and accurate system in place that ensures unique identification of tis-sues throughout the banking process, from receipt to distribution?

Yes No N/A Is there a system of vigilance and a procedure for recall and adverse events/reactionsavailable? Yes No N/A


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Do the actions taken include tracing of all relevant tissues, and where applicable, includetrace-back (to identify donor causing the reaction in the recipient)?

Yes No N/A Does this procedure contain at least the process to trace data:- From the tissue to the full donor records (including medical and behavioural his-

tory, testing, procurement and release)? Yes No N/A - Throughout processing and storage (including identification of equipment and

reagents used)? Yes No N/A - From the recipient to the donor-(tissue)? Yes No N/A - From the tissue at risk to all other distributed tissues from the same donor, and/or

the same batch? Yes No N/A - Are the names of the medical facilities and the recipients available?

Yes No N/A Is the information set in Annex VI of Directive 2006/86/EC kept by the TE?

Yes No N/A Is data kept for at least 30 years after clinical use? Yes No N/A Is traceability supported by adequate labelling? Yes No N/A Is traceability supported by adequate computer systems? Yes No N/A Does the end-user provide the TE with a follow-up form on the reception and trans-plantation of tissues? (recommendation) Yes No N/A Does the TE know the date of distribution/disposal? Yes No N/A Does the TE know the identity of clinician or end-user facility? Yes No N/A Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________

A.6 PERSONNEL TRAINING AND QUALIFICATION

STANDARD: Personnel directly involved in the donation, procurement, testing, processing,

preservation, storage and distribution of tissues and cells should be qualified toperform such tasks and provided with timely and relevant training (including train-ing manuals). The TE Quality System should have a function matrix in which re-sponsibilities and educational level and, if necessary, the possession of diplomasper function are defined.

The Quality System should be responsible for:- A procedure to check whether new personnel to be hired fulfil the criteria

set for that specific function.- Idem for personnel already under contract, when changing a function.- A procedure for introducing personnel into a new function (retraining).


35


- An induction procedure which contains information and education.- A continuous educational process and budget for education of personnel at

different levels. On-the-job training must be documented.- Adequate personnel files with up-to-date job descriptions, copies of required

diplomas and educational history. Competence of each TE member must bedocumented and assured.

The training programme must ensure and document that each individual:- Demonstrates competency in his/her designated tasks.- Has adequate knowledge and understanding of technical processes and their

tasks, the organisational framework, quality system and health and safety rules.- Is informed of the ethical, legal and regulatory context of his/her work.

AUDIT GUIDANCE:Meet with the person in charge of hiring new personnel and check how the

procedure is carried out. Check training and retraining system and instruction pro-cedure. Select three personnel files at random and check that on-the-job trainingand competence is documented, and personnel’s up-to-date job descriptions, ed-ucational history and diplomas are included.

CHECKLIST: Personnel Training and Qualification

Does the Quality System have a function matrix in which responsibilities and educationlevel of personnel are defined? Yes No N/A

If necessary, is the possession of diplomas per function defined?Yes No N/A

Are there training manuals available for the personnel? Yes No N/A Does the Quality System cover the following?

- A procedure to check whether new personnel to be hired fulfil the criteria set for thatspecific function Yes No N/A

- Idem for personnel already under contract, when changing a functionYes No N/A

- A procedure for introducing personnel into a new function (retraining) Yes No N/A

- An induction procedure which contains information and education Yes No N/A

- A continuous educational process and budget for education of personnel at differ-ent levels Yes No N/A

- Adequate personnel files with copies of required diplomas and educational historyYes No N/A


36


- Is on-the-job training documented? Yes No N/A - Is competence of each TE member documented? Yes No N/A

Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________

A.7 HEALTH & SAFETY OF STAFF; COMPLIANCE WITHLEGAL REQUIREMENTS

STANDARD:Necessary measures shall be in place for the protection of the personnel’s

health and safety throughout the entire tissue banking process. The TE must comply with the following legal requirements: - Display of Health and Safety member state law and contacts, as required by

local legal rules- Specific training given to staff regarding health and safety- Risk assessment carried out for activities undertaken- Evidence of risk reduction in place- Caution signage where appropriate- PPE available for staff and in use- Specific monitoring and controls for nitrogen storage where appropriateThere should be a procedure for accidental cuts during procurement or pro-

cessing, as well as for the subsequent testing and treatment of the staff memberwho has been cut or otherwise been in contact with donor blood during the pro-curement or processing.

AUDIT GUIDANCE:Identify the facility personnel responsible for these activities. If possible, au-

ditors should observe personnel for use of protective clothing and biosafety pre-cautions. Observe caution signage and nitrogen storage monitoring and control.Examine a few employee files at random for compliance and training in radiation,biological and chemical safety, as well as risk assessment. Review documentationto check whether there is a procedure for accidental cuts during procurement orprocessing, as well as for the subsequent testing and treatment of the staff mem-ber who has been cut or otherwise been in contact with donor blood during theprocurement or processing.


37


CHECKLIST: Compliance with the legal requirements for the protec-tion of the health and safety staff.

1. Display of Health and Safety member state law and contacts:- H&S law displayed, according to national regulations Yes No N/A - H&S notices displayed Yes No N/A - Access to occupational health services Yes No N/A - Access to confidential care services Yes No N/A

2. Specific training given to staff regarding health and safety:- Staff induction includes basic H&S training Yes No N/A - Advanced training in specific areas of practice Yes No N/A

3. Risk assessment carried out for activities undertaken:- Risk assessment performed: general, substances, manual handling, computer screen

working etc. Yes No N/A - Assessments reviewed on a regular basis Yes No N/A - New practices include review of risk assessments Yes No N/A - Particular arrangements in place for young, pregnant, disabled workers/visitors

Yes No N/A

4. Evidence of risk reduction in place:- SOPs include steps to safer practice Yes No N/A - Actions to reduce risk identified in risk assessment undertaken Yes No N/A - Code of practice for laboratory work including clothing policy, etc. Yes No N/A - Risk assessment conducted prior to contractor working Yes No N/A

5. Caution signage where appropriate:- Fire routes clearly signed Yes No N/A - Fire extinguishers present, fire doors closed Yes No N/A - Hazardous equipment/substances signage Yes No N/A - PPE signage where appropriate Yes No N/A - Restricted access to risk areas where required Yes No N/A

6. PPE available for staff and in use:- PPE (lab coats/gloves/masks, etc.) available for staff and visitors

Yes No N/A

7. Specific monitoring and controls for nitrogen storage where appropriate:- Specific nitrogen room working procedure/policy Yes No N/A - Room oxygen monitors Yes No N/A


38


- Personal oxygen alarms (recommended) Yes No N/A - Restricted access in the event of alarm Yes No N/A - Nitrogen shutdown procedure Yes No N/A - Breathing apparatus available if room accessed in alarm status Yes No N/A - Specific documented staff training in nitrogen working Yes No N/A


A.8 PACKAGING AND LABELLING

STANDARD: Packages, containers and labels must be validated as fit for purpose, specified

and treated as a critical item, and specified in SOP manual. SOPs must describemethods for testing and sterilising containers and packages, and specify that theproduct is preserved and stored safely. Packages must keep the tissue at the requiredtemperature during the defined period of time: preservation conditions must beguaranteed; the manner in which tissues/cells are packaged after procurement mustalso minimise the risk of contamination. Strength and impact resistance of the pack-aging (and labelling) must be adequate for the storage and transport methods used.Packaging must be capable of maintaining integrity, quality, function and sterility ofproduct. Package sealing must be effective and water/airtight. Labelling must be re-sistant to physical influences such as water. SOPs must be designed and followed inorder to show that correct labels and labelling are used for tissue identification.Labelling must correspond with data protection, anonymity and traceability. Duringdonation and procurement, accompanying tissue or blood samples for testing (ifany) must be accurately labelled to ensure identification with donor (including recordof time and place the specimen was taken).

Transportation conditions must be validated. These conditions must be definedand secured in the accompanying documentation. The selected transport companiesmust fulfil these criteria.

Each label must include at least the elements detailed in the following table:


39


Table 1: Label Contents

AUDIT GUIDANCE:Verify that labels and labelling are in accordance with the corresponding SOP.

Observe where labels are stored and verify that they are organised in a way that pre-vents errors. Select four package containers at random and check their integrity,quality and function. Check that labelling is resistant to water and that it shows es-sential information, including phrases such as “dry ice”, “this side up”, “handle withcare”, “human tissue for transplantation” and/or “biohazard” if applicable. Verifythat the labels in use meet the requirements listed in the table above (Table 1).

EELEMENT

LLabel l ing at

ccompl etion

oof

DDonation

LLabel l ing at

ccompl etion

oof Ret rieval

LLabel

dduring

PProcess ing

LLabel at

ccompl etion

oof

PProcess ing

LLabel at

DDistributio

nn

IInner &

OOuter

sshipping

ccontainer

llabel

Donor and product unique ID

number/code or batch/lot code X X X X X

Type of tissue/product X X X X X

Expiry date X X

Biological Hazard warning, if

applicable X X X X

Statement “for autologous use

only”, if applicable X X X

Patient identifiers for directed

use, if applicable X X

Description and dimensions of

product X X

Morphology/functional data, if

applicable X X

Date of Distribution of product X X

Biological determinations and

results X X

Opening, handling, thawing

reconstitution instructions X X

Storage recommendations X X

Expiry dates after opening X X

Mechanism for Adverse

Event/Reaction reporting X X

Presence of potential harmful

residues if applicable X X

Follow-up form with each

individual tissue (recommend) X

Name, address and phone

number of shipping facility X X X

Name, address, phone number

and contact person of intended

receiving facility X

Statements “Containing Human

Tissue” and “Handle with Care” X

Date and time of start of

transportation X

Recommended transport

conditions X

Safety instructions and method of

thawing when applicable X


40


Confirm that labels:- are correctly fixated to the package (and/or tag)- are positioned properly- are identical to the ones in SOP- are legible and accurate- have unique identification code firmly fixated to the product package, and

that this code is identical to the one in the TE’s associated forms- are not damaged or spoilt- in which there is hand written data, it is done so with permanent ink

CHECKLIST: Packaging and Labelling

1. PackagingAre all packages and containers validated as fit for purpose? Yes No N/A Are all labels validated as fit for purpose? Yes No N/A Is there control of packaging and labels as critical products? Yes No N/A Is packaging specified in product specification, if relevant? Yes No N/A Are contingencies validated for use in the event of supply failure? Yes No N/A Are methods to test and sterilise containers and packages described in SOPs?

Yes No N/A Are products preserved and stored safely, as described in SOPs? Yes No N/A Does the TE keep the tissue at the required temperature during the defined period oftime (are preservation conditions guaranteed)? Yes No N/A Is the packaging capable of maintaining integrity, quality, function and sterility of theproduct? Yes No N/A

Yes No N/A Is the strength and impact resistance of the packaging and labelling adequate for the stor-age and transport methods used? Yes No N/A Are tissues packaged using a standard method, if relevant? Yes No N/A Are packaged tissues shipped in containers suitable for the transport of biological mate-rials and which maintain their safety and quality? Yes No N/A Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________

2. Labelling - GeneralAre correct labels and labelling used for tissue identification, as defined in SOPs?

Yes No N/A Does labelling comply with data protection and anonymity, and traceability?

Yes No N/A


41


Does labelling show essential information such as “dry ice”, “this side up”, “handle withcare”, “human tissue for transplantation”… Yes No N/A Is the label resistant to water? Yes No N/A During donation and procurement, are accompanying tissue or blood samples for testing(if any) accurately labelled? Yes No N/A Does the sample label include a record of the time and place the specimen was taken?


3. Procurement Container Is each tissue segment packaged individually as soon after retrieval as possible, using ster-ile containers? Yes No N/A Are appropriate reagents or preservative solutions used, as specified in SOPs?

Yes No N/A Is integrity of the container maintained after filling and closing? Yes No N/A Is labelling of tissues or blood samples accurate and does it include a record of the timeand place the specimen was taken? Yes No N/A At the time of retrieval, is every package containing tissue labelled with at least the fol-lowing data?

- Donor and donation identification/code Yes No N/A - Type of tissue Yes No N/A

Do the container labels comply with additional requirements established by common car-riers or by inter-governmental, national, regional, and local regulations or laws?

Yes No N/A Are transportation conditions defined, secured and validated? Yes No N/A Do selected transport companies fulfil these criteria? Yes No N/A Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________


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4. Fit-for-use products are labelled with (primary packaging):- Product, unique ID number/code or batch/lot number/code

Yes No N/A - TE name, address and phone number Yes No N/A - Expiry date Yes No N/A - If applicable, autologous and patient identifiers Yes No N/A - If applicable, patient identifiers for directed use Yes No N/A - If applicable, biological hazard if positive for infectious disease. Yes No N/A


5. Fit-for-use products are labelled with (packaging or accompanying documentation):- Description and dimensions Yes No N/A - If applicable, morphology/functional data Yes No N/A - Date of distribution Yes No N/A - Biological determinations and results Yes No N/A - Storage recommendations Yes No N/A - Opening/handling/reconstitution instructions Yes No N/A - Expiry after opening Yes No N/A - Mechanism for adverse event reporting Yes No N/A - Presence of harmful residues Yes No N/A


6. Shipping container is labelled with: - Name, address and phone number of shipping facility Yes No N/A - Name, address, phone number and contact person of intended receiving facility

Yes No N/A - Statements “Containing Human Tissue” and “Handle with Care” Yes No N/A - Date and time of start of transportation Yes No N/A - Recommended transport conditions Yes No N/A - Safety instructions and method of thawing when applicable Yes No N/A - “For autologous use only” label in case of autologous donors Yes No N/A - Biological hazard warning, if applicable Yes No N/A



43


A.9 RECORDS AND REGISTERS

STANDARD:

The TE must have a record keeping system in place for all its activities which results indefined and effective documentation, correct records and registers, and authorised SOPs.Records of each donation procedure and all tissues retrieved shall be available and kept bythe tissue bank.

The system must ensure that all work performed is standardised and that all steps aretraceable: coding, donor suitability, procurement, processing, preservation, storage, transport,distribution or disposal, aspects relating to quality control and assurance, personnel trainingand competency, facility maintenance and management, and other general facility issues.

Standardised forms respecting local conditions and regulations shall be used.There must be a document control procedure (as well as one for the review of changes

to documents). All records must:- be regarded as privileged and confidential information- be legible and permanent- be maintained so as to ensure their integrity and preservation- allow identification of the person and equipment responsible for and involved in each

step - include dates- show test results and interpretation- determine lot numbers and manufacturer of supplies and reagents used- be kept in order to ensure access to the data for at least 30 years after expiry date, clin-

ical use or disposal, or in accordance with applicable inter-governmental, national, re-gional or local laws or regulations

There must also be registers of recipients and they must / should correspond withthe following criteria:

- Name of ordering person- Name of hospital, department and ward of hospital of end user- If available, purpose/disease, implantation location of the graft- Archiving for 30 years- Separated from donor file- Anonymous traceability data as in previous chapters- Name of physician in charge- Name, personal identification data of recipient (if available)Data protection and confidentiality measures shall be in place according to Article 14

of Directive 2004/23/EC.For specific requirements of donor and procurement documentation please see sec-

tions B.3 and C.3 respectively.


44


AUDIT GUIDANCE:

Verify that the record keeping system is documented and includes at least thefollowing:

- Location of new and completed forms- Method of error correction- Method to prevent destruction or loss of the record- Method of documenting modifications and distribution- Time of retention and proper storage location- System to ensure confidentiality of records- Methods for filing and transfer of records to archival storageWith regard to donor files, be alert to breaches in policy that potentially compromise

donor confidentiality (unsecured patient records; patient charts left unattended in areaswhere restricted personnel and/or visitors may have access, or unattended computer screensdisplaying patient information in these areas; patient information posted on bulletin boardswhich are potentially visible by non-medical staff; release of confidential information with-out appropriate consent, etc.). Check that release for transplantation is done by responsiblemedical officer and quality assurance officer.

With regard to recipient archives, select four of them at random and verify that the in-formation stated in this standard is included.

CHECKLIST: Records and Registers

Does the TE have a system in place for defined and effective documentation, correctrecords and registers and authorised SOPs? Yes No N/A Does the system in place ensure that all work performed is standardised and that all stepsare traceable? Yes No N/A Are the forms standardised and do they respect local conditions and regulations?

Yes No N/A Are all the following steps/activities adequately recorded?

- coding Yes No N/A - donor suitability Yes No N/A - procurement Yes No N/A - processing Yes No N/A - preservation Yes No N/A - storage Yes No N/A - transport Yes No N/A - distribution or disposal Yes No N/A - quality control and assurance Yes No N/A - personnel training and competence Yes No N/A - facility maintenance and management Yes No N/A


45


Is there a document control procedure? Yes No N/A Are the changes to documents periodically reviewed? Yes No N/A

Does the recipient register meet the following criteria?- Separated from donor file Yes No N/A - Anonymous traceability data Yes No N/A - Name of physician in charge Yes No N/A - Name of ordering person Yes No N/A - Name of hospital, department and ward of hospital of end user

Yes No N/A - Name, personal identification data of recipient (if available) Yes No N/A - If available, purpose/disease, implantation location of the graft

Yes No N/A - Archiving for 30 years Yes No N/A

Are all records / Do all records?- regarded as privileged and confidential information Yes No N/A - legible and indelible Yes No N/A - maintained so as to ensure their integrity and preservation Yes No N/A - allow identification of the person responsible for each step Yes No N/A - include dates Yes No N/A - show test results and interpretation Yes No N/A - determine lot numbers and manufacturer of supplies and reagents used

Yes No N/A - kept in order to ensure access to the data for at least 30 years after expiry date, clin-

ical use or disposal, or in accordance with applicable inter-governmental, national,regional or local laws or regulations



46


PART B: TISSUE DONATION

B.1 DONOR SELECTION AND EVALUATION

STANDARD: Donor selection and evaluation shall be performed by trained personnel and

described in detail in SOPs. There shall be SOPs for the verification of donoridentity, donor/family consent, assessment of selection criteria for deceased andliving donors and assessment of laboratory tests required. All consent required bylocal legislation and regulations shall be obtained.

The following list of actions for donor selection and screening shall be veri-fied and shall include: Donor identity, donor consent details, medical history requirements,assessment of selection criteria and behavioural risks, detailed physical examination and as-sessment of laboratory testing results. For living donors, an interview must be con-ducted during which a questionnaire is completed (e.g. face-to-face or phoneinterview). For deceased donors, alternative sources of information must be used.The cause, time and circumstances of death shall be recorded. A donor age cri-teria shall be established, documented and recorded.

Donors shall be excluded from donation if any of the circumstances shownin Technical Annex 1 of Directive 2006/17/EC apply (see list on page 48).

AUDIT GUIDANCE:Verify that a face-to-face interview is conducted with living donors by speak-

ing to the person in charge and by examining the questionnaire completed duringthe interview. For deceased donors, review the sources of information used.

Donor identity: Review identification procedure and by whom it is carriedout.

Donor consent details: Authorised person who confirms and records thatthe consent has been obtained in accordance with the legislation in place in theMember State. Check that all consents required by local regulations and legislationare obtained. For living donor, verify that the informed consent includes notifi-cation of all reasonable risks and potential harm, as well as tests to be performed.Verify that the request for donation is explained in understandable terms by ahealth care professional familiar with the donation process.

Medical history requirements/ Assessment of behavioural risks/Physical examination forms: Review Medical History form to confirm that ad-equate information is sought to allow the application of the exclusion criteria inTechnical Annex 1 of Directive 2006/17/EC. Select four donor records at randomto examine the evidence that all the exclusion criteria have been appropriately in-vestigated and applied. Check that information regarding the donor’s behavioural


47


history (increasing the risk of transmissible diseases) is explored. Physical exam-ination forms: verify that key points are always answered (never blank), and if an-swered “yes”, an explanation is given. Verify that any signs that may be sufficientin themselves to exclude the donor are detected, giving special attention to tu-mours, infections, risk factors for transmissible diseases, traumas to the donor’sbody and scars from recent or old operations.

Assessment of testing results: Check that the notification of confirmedpositive test results is carried out.

CHECKLIST: Donor Selection and Evaluation

1. GeneralIs donor selection and evaluation performed by trained personnel? Yes No N/A Are there SOPs for the verification of the assessment of the selection criteria for donors?

Yes No N/A Auditor: Check reference Is there a person responsible for donor selection and evaluation? Yes No N/A Does an authorised person collect all donor documentation needed?

Yes No N/A For living donors, is an interview conducted? Yes No N/A Is a questionnaire used during this interview? Yes No N/A For deceased donors, are alternative sources of information used? Yes No N/A For deceased donors, are the cause, time and circumstances of death recorded by the fa-cility? Yes No N/A Auditor: Verify with donor documentation.Is a donor age criteria established, documented and recorded? Yes No N/A Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________

2. Donor IdentityIs donor identification detailed in and in accordance with SOPs? Yes No N/A Is there a person responsible for the donor identification? Yes No N/A Is donor identification confirmed and recorded? Yes No N/A Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________


48


3. Donor Consent DetailsAre there SOPs for the verification of donor or donor family consent?

Yes No N/A Is there an authorised person who confirms and records that the consent has been ob-tained in accordance with the legislation in place in your Member State?

Yes No N/A Verify that the facility has consents required by local regulations and legislation.

Yes No N/A For living donors, does the informed consent include notification of all reasonable risks,potential harm and tests to be performed? Yes No N/A Is the request for donation explained in understandable terms by a health care profes-sional familiar with the donation process? Yes No N/A Is informed consent obtained in accordance with procedures? Yes No N/A Auditor Comments: __________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

4. Medical History RequirementsDonors are generally excluded from donation if any of the following conditions exists:

- Unknown cause of death, unless autopsy provides information on the cause of death after pro-curement and none of the general criteria for exclusion below applies.

Yes No N/A - Past history of a disease of unknown aetiology. Yes No N/A - Presence or previous history of malignant disease (except primary basal cell carcinoma, carci-

noma in situ of uterine cervix, and some primary tumours of the CNS). Yes No N/A

- Risk of transmission of disease caused by prions, including Creutzfeldt-Jakob disease, rapid pro-gressive dementia or degenerative neurological disease, recipients of hormones derived fromhuman pituitary gland and recipients of grafts of cornea, sclera and dura mater, and personswho have undergone undocumented neurosurgery, where dura mater may have been used. Forvariant Creutzfeldt-Jakob disease, further precautionary measures may be recommended.

Yes No N/A - Systemic bacterial, viral, fungal or parasitic infections not controlled at time of donation, or sig-

nificant local infection in tissues to be donated. Yes No N/A - History, clinical evidence or confirmed positive laboratory tests for HIV infection, acute or

chronic hepatitis B or hepatitis C infection or HTLV I/II infection, or history of risk factors forthese infections. Yes No N/A

- History of chronic, systemic autoimmune disease that could have a detrimental effect on thequality of the tissue to be retrieved. Yes No N/A


49


- Presence of sufficient haemodilution of donor blood samples to make testing invalid and alsodue to treatment with immunosuppressive agents. Yes No N/A

- Evidence of any other risk factors for transmissible diseases on the basis of a risk assessment,taking into consideration donor travel and exposure history and local infectious disease preva-lence. Yes No N/A

- Presence in donor’s body of physical signs implying a risk of infection with transmissible dis-ease(s). Yes No N/A

- Ingestion of or exposure to a substance that may be transmitted to recipients in a dose thatcould endanger their health. Yes No N/A

- Recent history of vaccination with a live attenuate virus where a risk of transmission is consid-ered to exist. Yes No N/A

- Transplantation with xenografts. Yes No N/A - Children less than 18 months old born from mothers with HIV, hepatitis B, C or HTLV infec-

tion, or at risk of such infection, and who have been breastfed by their mothers during the pre-vious 12 months, cannot be considered as donors regardless of the result of the analytical tests.

Yes No N/A - Children born from mothers with HIV, hepatitis B, C or HTLV infection, or at risk of such in-

fection, and who have NOT been breastfed by their mothers during the previous 12 monthsand for whom analytical tests, physical examinations and reviews of medical records do not pro-vide evidence of HIV, hepatitis B, C or HTLV infection, can be accepted as donors.

Yes No N/A - Additionally for living donors, exclusion if the donor is a mother breastfeeding or pregnant (ex-

cept for donors of umbilical cord blood cells and amniotic membrane). Yes No N/A Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________

5. Assessment of Behavioural RisksIs there a questionnaire in which information regarding the donor’s behavioural attitude(increasing risk of transmissible diseases) is recorded? Yes No N/A Is the person answering medical, social and sexual inquiries about the donor eligibleto do so? Yes No N/A Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________

6. Physical Examination RequirementsAre cadaveric donors subject to a physical examination prior to retrieval?

Yes No N/A


50


In the physical examination form, are key points always answered (never blank)?Yes No N/A

When the answer is “Yes” (on the form), is an explanation given?Yes No N/A

Is the body examined to detect any signs that may be sufficient in themselves to excludethe donor? Yes No N/A Verify that special attention is given to the following:

- Tumours Yes No N/A - Infections Yes No N/A - Risk factors for transmissible diseases Yes No N/A - Traumas to donor’s body Yes No N/A - Scars from recent or old operations Yes No N/A


7. Assessment of Testing ResultsDoes the facility have and comply with SOPs for the assessment of laboratory tests re-quired for donors? Yes No N/A Are donor’s next of kin or physician notified in accordance with state laws of confirmedpositive results having clinical significance? Yes No N/A Are confirmed positive donor infectious disease tests reported to health authorities?

Yes, local health authority Yes, national health authority No N/A How does the notification proceed for living donors and cadaveric donors?Living donors: ________________________________________________________________________________________________________________________________________________________________________________________________Cadaveric donors:______________________________________________________________________________________________________________________________________________________________________________________________Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________

B.2 DONOR CODING

STANDARD:By September 2008, all MS must allocate a unique European identifying code

to all donated material at the tissue establishment, to ensure proper identificationof the donor and the traceability of all donated material as well as to provide in-


51


formation on the main characteristics and properties of tissues. An in-house coding system, as long as it is unique internationally, is sufficient.

Verbal description of the tissue graft, as long as it is unambiguous, is also suffi-cient. With respect to donor identification, nationally applied principles and pro-cedures are acceptable (for example using name and ID when tissue retrieval andusage occur within a single health care unit, or in IVF clinics for partner donation).

The code shall incorporate at least the information shown in the EuropeanDirective 2006/17/EC, Annex VII (see section C.1). With regards to donationinformation, the code must incorporate the following:

- unique ID number- identification of the TE

AUDIT GUIDANCE:Review the donor coding system in place at the TE and check that the fol-

lowing information is incorporated: unique ID number, identification of the TE.

CHECKLIST: Donor Identification and Coding

Do the donor selection and evaluation staff allocate a unique identification code to thedonor? Yes No N/A Is a unique European identifying code allocated to all donated material at the TE, if sucha coding exists? Yes No N/A Does the code incorporate at least the following information?

- Unique ID number Yes No N/A - Identification of the TE (and country/city) Yes No N/A


B.3 DONOR TESTING

STANDARD: Donor Testing shall be performed by a qualified laboratory, authorised or ac-

credited as a testing centre by the competent authority in the Member State, usingEC-marked testing kits where appropriate. The type of test used must be vali-dated for the purpose in accordance with current scientific knowledge. Thereshould be written agreements with the laboratory providing its services.Algorithms shall be in place and shall be followed in the case of positive testingresults in certain parameters. Serological tests required for the donors shall in-


52


clude: Anti HIV 1 and 2, HBsAg, Anti HBc, Anti HCVAb, testing for syphilis(Annex II Directive 2006/17/EC). For testing of donors of reproductive cellsAnnex III of the same directive shall apply.

Serological tests shall be carried out on donor’s serum or plasma. For de-ceased donors, blood samples should be obtained prior to death or if notpossible, within twenty-four hours of death. For living donors, blood samplesshould be obtained at the time of donation or, if not possible, within sevendays post donation.

AUDIT GUIDANCE:Verify that serological tests required for the donors include: Anti HIV 1 and

2, HBsAg, Anti HBc, Anti HCVAb and testing for syphilis. Check that blood sam-ples are obtained as a maximum twenty-four hours after death for cadavericdonors, and seven days post donation for living donors unless it is possible to ob-tain it at the time of donation.

Verify that appropriate investigations are carried out to ensure that blood sam-ples used for testing are not diluted by prior transfusions or infusions so as torender the test result invalid.

CHECKLIST: Donor Testing

1. Transmissible Diseases Blood Testing and Microbiological Testing of DonorIs tissue donor testing for transmissible microbiological diseases in compliance with thelaw or practice in the country? Yes No N/A Is donor testing performed by a qualified laboratory, accredited or authorized as a testingcentre by the competent authority? Yes No N/A Is the type of test used validated for the purpose in accordance with current scientificknowledge? Yes No N/A Is there a written agreement with the contracted laboratory?

Yes No N/A Are algorithms in place and are they followed in the case of positive testing results in cer-tain parameters? Yes No N/A Are the following serological tests performed for all donors (minimum require-ment)?

- HIV Antibodies 1 and 2 Yes No N/A - HBsAg Yes No N/A - HBcAb (total) Yes No N/A - HCV-Ab Yes No N/A - Syphilis: treponemal test (e.g. TPHA, TPPA) Yes No N/A

Are serological tests performed on donor’s serum or plasma? Yes No N/A


53


For deceased donors, are blood samples obtained prior to death, or if not possible, withintwenty-four hours of death? Yes No N/A For living donors, are blood samples obtained at the time of donation?

Yes No N/A If not possible, are they obtained within seven days post donation?

Yes No N/A Is remaining donor serum securely sealed and stored frozen in a proper manner?

Yes No N/A If yes, is there a record that states for how many years it will be stored, after the expirydate of the tissue? (recommended, although not required) Yes No N/A

Are additional necessary blood tests performed? Yes No N/A Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________

B.4 DONOR DOCUMENTATION

STANDARD: There must be a record/form for each donor which must include at least the

following information: - donor identification- age- sex- cause of death (time and circumstances also recommended)- medical and social history- relevant clinical data- consent form- body examination results- procurement report- haemodilution formula- laboratory and other test results- autopsy/biopsy results, if applicable

Records shall be in compliance with data protection legislation, and shall belegible and permanent. Data protection and confidentiality measures shall be inplace according to Article 14 of Directive 2004/23/EC.

For general requirements of documentation please see section A.9.


54


AUDIT GUIDANCE:Select four donor records at random to examine that all the information stated

in this standard is explored and recorded. Verify that for all this criteria, the per-son responsible is given.

CHECKLIST: Donor Documentation

Does the TE keep donor registers? Yes No N/A Does it archive them for a period of at least 30 years? Yes No N/A Does each donor have a unique record? Yes No N/A Does the donor record/form include?

- Donor identification (identification procedure) Yes No N/A - Age Yes No N/A - Sex Yes No N/A - Cause of death Yes No N/A - Medical and social history (sources of info. and data lacking)

Yes No N/A - Clinical data (haemodilution formula – time and date of sampling)

Yes No N/A - Consent form Yes No N/A - Body examination results (drawing, correlation between body examination and med-

ical/social history) Yes No N/A - Procurement results (date and time of beginning and end of retrieval)

Yes No N/A - Haemodilution formula Yes No N/A - Laboratory (and other) test results (time and date of sampling)

Yes No N/A - Autopsy/biopsy results, if applicable (time and date) Yes No N/A

Are data protection and confidentiality measures in place, according to Article 14 ofDirective 2004/23/EC? Yes No N/A Are they legible and permanent? Yes No N/A Are donor’s clinical records maintained for at least 30 years? Yes No N/A Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________


55


PART C: TISSUE PROCUREMENT

C.1 GENERAL PRINCIPLES

STANDARD: SOPs, Informed Consent, Donor Identification and CodingFacility shall have SOPs describing the procedures for procurement of tis-

sues and cells.The positive identification of the donor must be performed prior to pro-

curement. There must be a system in place for the identification of human tissuesand cells to guarantee traceability. The code shall incorporate at least the infor-mation shown in the European Directive 2006/17/EC, Annex VII, which is asfollows:

- Donation Information: unique ID number and identification of the TE- Product Identification: product code, split number and expiry date

For more information on donor coding see section B.2.Consent must be given for tissue procurement by the responsible person.

AUDIT GUIDANCE:Review the donor and product coding system in place at the TE and check

that the following information is incorporated: unique ID number, identification of theTE, product code, split number and expiry date.

Speak with person responsible for donor identification before procurementand ask for explanation of how donor is identified.

Verify in the procurement report / donor file that consent for tissue retrievalis obtained by the responsible person.

CHECKLIST: General Principles

1. SOPs for ProcurementDoes the facility have SOPs for:

- The verification of donor identity? Yes No N/A - The confirmation of donor/donor family consent? Yes No N/A - Assessment of donor eligibility? Yes No N/A

Do the SOPs describe the procedures for procurement? Yes No N/A

2. Informed ConsentBefore tissue retrieval, is informed consent ensured by staff and documented?

Yes No N/A


56


3. Donor Identification and CodingDo retrieval staff verify positive donor identity? Yes No N/A Is there a system in place for the identification of human tissues and cells?

Yes No N/A Is a unique European identifying code allocated to all donated material at the TE, if sucha coding exists? Yes No N/A Does the facility ensure that a unique donor identification number is assigned to eachdonor? Yes No N/A

Does the code incorporate at least the following information?· Donation identification:

- Unique ID number Yes No N/A - Identification of the TE (and country/city) Yes No N/A

· Product identification:- Product code (basic nomenclature) Yes No N/A - Split number (if applicable) Yes No N/A - Expiry date Yes No N/A


C.2 RETRIEVAL CONDITIONS

STANDARD: Tissue procurement shall be performed in suitable rooms by qualified and trained

personnel, using validated equipment and methods described in detail in SOPs. All pro-curement procedures shall be validated. For living donors, procurement must occur inan environment which ensures their health, safety and privacy. All equipment and in-struments used shall be validated, and sterilized between procurements, according to avalidated method. Sterile single-use instruments shall be used whenever possible. Aseptictechnique shall be used throughout the procurement procedure. During clean, non-sterile procurement, allografts are suitable for transplantation if efficient, validated ster-ilising methods are used to eliminate pathogens after retrieval. Samples formicrobiological testing shall be taken where applicable.

AUDIT GUIDANCE:Personnel and Facilities: Select four procurement personnel profiles and

check qualification of workers. Meet personnel and visit procurement rooms, iffeasible. Verify that personnel clothing and hygiene are adequate.

Equipment: Check lot number and expiry date of sets of equipment,


57


reagents and mediums. Check quality and sterility of equipment.Retrieval Techniques and Prevention of Contamination: During clean,

non-sterile procurement, check sterilising methods used and their validation.Microbiological Testing of Tissues Retrieved: Check the identification

of samples taken. Verify that the date of sampling is recorded. (Recording timeof beginning and end of retrieval is important, as sampling is routinely done dur-ing retrieval, before packaging the tissue). For live donations (surgical residues) itis enough to be able to track down the time of the operation.

CHECKLIST: Retrieval Conditions

Verify that the following key points are included and described in detail in SOPs.

1. General Time LimitsAre tissue procurement methods described in sufficient detail in SOPs?

Yes No N/A Are all procurement procedures validated? Yes No N/A For living donors, does procurement occur in an environment which ensures their health,safety and privacy? Yes No N/A Are procurement personnel adequately trained to retrieve tissues within specified timelimits? Yes No N/A Does the SOP manual indicate the time limits for post-mortem retrieval of tissues?

Yes No N/A Do staff adhere properly to time limits? Yes No N/A Is there a policy for cases where retrieval is delayed for cadaveric donors?


2. FacilitiesDo qualified and trained personnel perform procurement in validated and appropriate fa-cilities? Yes No N/A Are the environmental conditions of these facilities adequate and as described in SOPs?



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3. Equipment Are single-use instruments used during procurement? Yes No N/A If no, are all instruments and equipment sterilised between procurements, according to avalidated method? Yes No N/A Check lot number and expiry date of equipment, reagents and mediums.Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________

4. Retrieval Techniques and Prevention of ContaminationThroughout the procurement procedure, is aseptic technique observed? Yes No N/A During aseptic procurement, are procurement sites prepared using a standard surgicalpractice? Yes No N/A Are all methods consistent with standard operating room practice? Yes No N/A During clean non-sterile procurement, are efficient validated sterilising methods used toeliminate pathogens after retrieval? Yes No N/A Note: in this case, allografts are suitable for transplantation.Does TE ensure that tissues are not contaminated during the retrieval? Yes No N/A For living donors, are tissues removed under conditions which represent the least possi-ble risk to the donor, and in properly equipped and staffed institutions?


5. Microbiological Testing of Tissues RetrievedIf samples for microbiological cultures are obtained at the time of retrieval, are samplesof each retrieved tissue taken prior to exposure of the tissue to antibiotic or antiseptic con-taining solution? Yes No N/A Verify that the date of sampling is recorded.Does the culture technique allow the growth of both aerobic and anaerobic bacteria andfungi? Yes No N/A Are these testing results documented in the donor record? Yes No N/A Are there established bacteriological bioburden limits for tissue samples for permitted tis-sue distribution, regarding the degree of virulence of any microorganisms found on thesamples? Yes No N/A Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________


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6. Body Reconstruction of Cadaveric DonorsDoes the facility maintain a procedure for donor reconstruction? Yes No N/A Is the donor’s body reconstructed as closely as possible to its original anatomical shape?

Yes No N/A Do the SOPs and the trained staff ensure that donor reconstruction will be done prop-erly? Yes No N/A Does the facility maintain records on donor’s final disposition (applicable for TEs havingtheir own morgue/retrieval facilities? Yes No N/A Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________

C.3 RETRIEVAL DOCUMENTATION

STANDARD: The forms shall be filled in and signed by designated procurement team mem-

bers and checked and signed by a responsible person, or his/her assignee. Recordsof all tissues retrieved shall be available and kept by the tissue bank for at least 30years.

The minimum information in procurement records shall contain: - identification, name and address of the TE to receive the tissues/cells- donor identity (including how and by whom the donor was identified)- date, time (where relevant, start and end) and place of procurement and

procedure used. Where relevant, environmental conditions at the pro-curement facility

- identity of the person(s) performing the retrieval- identity and signature of the responsible procurement officer - description and identification of tissue(s)/cells retrieved (including sam-

ples for testing)- for deceased donors, conditions under which the cadaver is kept (re-

frigerated or not, time of start and end of refrigeration)- ID/batch numbers of reagents and transport solutions used- date and time of death where possible- date and time of procurement may be included, where possible- details of the physical examination form prior to retrieval where possi-

ble, in case of deceased donors- Where sperm is procured at home, the procurement report must state

this and must contain only the name and address of the TE to receivethe tissues/cells, and the identification of the donor

For general requirements of documentation please see section A.9.


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AUDIT GUIDANCE:Select four procurement reports and verify that the information stated in this

standard is observed. These reports must be filled in and signed by designatedprocurement team members and checked and signed by a responsible person, orhis/her assignee, and maintained for at least thirty years.

CHECKLIST: Retrieval Documentation

1. General – Procurement RecordsAre appropriate records of each donation procedure and of all tissues retrieved availableand kept by the tissue bank? Yes No N/A Do these standardised forms respect the local conditions and regulations?

Yes No N/A Are the forms filled in and signed by designated procurement team members?

Yes No N/A Are they checked and signed by a responsible person or his/her assignee?

Yes No N/A

2. DocumentationVerify that all retrieved tissues are provided with an accompanying form including at leastthe following information:

- Identification, name and address of the TE to receive the tissues/cells Yes No N/A

- Donor identity (including how and by whom the donor was identified)Yes No N/A

- Date, time (where relevant, start and end) and place of procurement and pro-cedure used. Where relevant, environmental conditions at the procurementfacility Yes No N/A

- Identity of the person(s) performing the retrieval Yes No N/A - Identity and signature of the responsible procurement officer Yes No N/A - Description and identification of tissue(s)/cells retrieved (including samples for

testing) Yes No N/A - For deceased donors, conditions under which the cadaver is kept (refrigerated or

not, time of start and end of refrigeration) Yes No N/A - ID/batch numbers of reagents and transport solutions used Yes No N/A - Date and time of death where possible Yes No N/A - Date and time of procurement may be included, where possible

Yes No N/A - Details of the physical examination form prior to retrieval, in case of deceased

donors Yes No N/A


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- Where sperm is procured at home, the procurement report must state this and mustcontain only the name and address of the TE to receive the tissues/cells, and theidentification of the donor Yes No N/A


C.4 TRANSPORTATION TO TE

STANDARD: Packing and transport conditions must be a validated procedure and

documented in SOPs.Transport shall be provided under conditions which minimise the risk

of contamination and guarantee the retaining of the original biologicalproperties of the tissues procured. Packaged tissues must be shipped in acontainer suitable for the transport of biological materials and which main-tains their safety and quality. Labelling of tissues or blood samples mustbe accurate, and must include a record of the time and place the specimenwas taken.

AUDIT GUIDANCE:Check for the presence of written procedures which verify that trans-

port conditions are validated and provided under the conditions stated inthis standard. Examine a few packaging containers and their labels and ob-serve their suitability and whether the safety of the products is maintained.

CHECKLIST: Transportation of Procured Tissue to Processing CentreIs the transportation provided under conditions which minimise the risk of contamina-tion and guarantee the retaining of the biological properties of the tissues procured?

Yes No N/A Are these conditions specified in the SOPs and are they validated? Yes No N/A Are procedures used to ensure and document proper temperature storage during transit?

Yes No N/A Has the contracted facility validated the packaging and transport conditions (tempera-tures) of frozen tissue shipped to the tissue bank? Yes No N/A If shipping container validation has not occurred, are there policies for the method of tem-perature monitoring? Yes No N/A Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________


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PART D: TISSUE PROCESSING

D.1 GENERAL PRINCIPLES

STANDARD: Tissue processing carried out according to SOPs: All processes must be

carried out according to validated, authorised SOPs which clearly describe theprocess and expected outcome. The Quality System must control the version inuse and evaluate its current validity (review). There must be staff training recordsto demonstrate staff continued competence/compliance with SOPs.

Unique tissue identification number: The bank shall have a unique codingsystem to ensure donor and tissue product identification and traceability, and it willcomprise:

Donation identification:- Unique ID number- Identification of the tissue establishment

Product identification:- Product code- Pack/split number if applicable- Expiry date

Reception policies for retrieved tissues at the processing/storage es-tablishment:

There must be documented verification that the consignment, including trans-port conditions, packaging, labelling and associated documentation and samples,meets the requirements of this guide and the specifications of the receiving es-tablishment. All tissue material must be tested according to the required testingregime. There must be a procedure to separate quarantine from “approved” tis-sue. The integrity of the outer packaging upon arrival must be intact.

Validation of the methods applied: All processes must be validated (lo-cally, published or retrospective evaluation) for effectiveness against the desiredoutcome. Where a defined specification limit is required (e.g. moisture level) thismust be assessed and recorded. Staff must be assessed for aseptic working (whereappropriate) using simulation qualification (e.g. media fill).

Pooling: There must be documented procedural control to avoid cross con-tamination from one donation to another. Where pooling of multiple donationsis permitted, it must be documented, risk assessed and justified.

Control and recording of key parameters (e.g. cooling curves, freeze-drying cycles…): Key parameters must be recorded and documented to cali-brated standards and approved as part of product release.

Specific processing procedures: It must be demonstrated that processes


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applied will not adversely affect either the clinical performance of the graft or therecipient.

AUDIT GUIDANCE:Verify that there are SOPs for tissue processing. Select two staff training

records at random and review that staff have continuing competence andcompliance with SOPs. Review the coding system. Select two processing re-ports at random and verify that they include the following data: unique ID num-ber, identification of the tissue establishment, product code, pack/split number if applicableand expiry date.

Verify that all the methods applied are validated and that processing pro-cedures are safe for the tissue and staff. Verify that there are written proce-dures for the control of cross-contamination, as well as for the control andrecording of key parameters. There must be a procedure to separate quaran-tine tissue from “approved” tissue.

CHECKLIST: General

1. Tissue processing prepared according to SOPs1.1. All processes will be carried out to validated, authorised SOPs which clearly describethe process and expected outcome.Do all processes have a documented and approved SOP? Yes No N/A Do SOP’s state their intended purpose and are they available to staff ?

Yes No N/A Is there evidence SOPs are validated prior to implementation? Yes No N/A Is there evidence that staff are only working to the described procedures?

Yes No N/A 1.2. The Quality System will control the version in use and evaluate its current validity (re-view).A document control procedure includes:

- SOP to control documents. Yes No N/A - Authorisation (Manager/Quality) system for documents. Yes No N/A - Minimum review period with evidence of compliance. Yes No N/A - System for ensuring the correct version is in use with evidence.

Yes No N/A 1.3. There will be staff training records to demonstrate staff continued competence andcompliance with SOPs.All staff have training records linked to SOPs. Yes No N/A All staff are assessed as competent and authorised to undertake a procedure before car-rying it out. Yes No N/A


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There is evidence of ongoing competence monitoring. Yes No N/A Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________

2. Unique tissue identification number2.1 The bank shall have a unique coding system with minimum dataset comprising:

- Unique donor identification Yes No N/A - ID of tissue establishment Yes No N/A - Product code Yes No N/A - Pack/split number if applicable Yes No N/A - Expiry date Yes No N/A

Are there mechanisms to ensure codes are only assigned to the appropriate tissues and can-not be mixed? Yes No N/A Are subsequent donation events linked? Yes No N/A How does the establishment guarantee that it is internationally unique?________________________________________________________________________________________________________________________________________Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________

3. Reception policies for retrieved tissues at the processing/storage esta-blishment.Does the shipment meet the specifications of the receiving establishment?

Yes No N/A Is there documented verification of this? Yes No N/A Is all tissue material tested according to the required testing regime?

Yes No N/A Is there a procedure to separate quarantine from “approved” tissue? Yes No N/A Is the integrity of the outer package intact upon arrival? Yes No N/A Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________

4. Validation of the methods applied4.1. All processes will be validated (locally, published or retrospective evaluation) for ef-fectiveness against the desired outcome.


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Does change control include validation steps to demonstrate desired outcome?Yes No N/A

Are validations approved by the Responsible Person or approved designate?Yes No N/A

Where long standing historic processes are not validated, is there documented retrospec-tive evaluation or published data to demonstrate validity of the process?

Yes No N/A

4.2. Where a defined specification limit is required, e.g. moisture level, this will be assessedand recorded.Where a process requires specified parameters, e.g. temperature, each process will be val-idated to routinely achieve the desired parameter:

- Controlled freezing rate Yes No N/A - Freeze drying Yes No N/A - Other (state)______________________________ Yes No N/A

Are parameters checked as part of normal authorisation? Yes No N/A

4.3 Staff will be assessed for aseptic working (where appropriate) using simulation quali-fication (e.g. media fill).Has aseptic working been validated by all staff, e.g. by media fill? Yes No N/A Auditor Comments: __________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

5. Pooling5.1. Avoidance of cross-contamination.Do staff only work with one batch at a time? Yes No N/A Is there a clean down between each batch? Yes No N/A Where batches are manipulated in the same environment is there evidence that cross con-tamination risk has been considered and minimised? Yes No N/A Does multiple donor pooling occur? Yes No N/A Justification: ______________________________________________________________________________________________________________________________Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________


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6. Control and recording of key parameters (e.g. cooling curves, freeze-dryingcycles)6.1 Key parameters will be recorded and documented to calibrated standards and approvedas part of product release.Where a process requires specified parameters each process will have documented proofof conformance to validate/approve each process.

- Temperature Yes No N/A - Moisture Yes No N/A - Other (state)_________________________ Yes No N/A


7. Specific processing proceduresIt must be demonstrated that processes applied will not adversely affect either the clinicalperformance of the graft or the recipient.Processes applied are validated for:

- Viability Yes No N/A - Mechanical effects Yes No N/A - Cytotoxicity Yes No N/A - Clinical performance review Yes No N/A


D.2 EQUIPMENT SUITABILITY, STERILITY ANDTRACEABILITY

STANDARD:Sterility, suitability and traceability of instruments, reagents and solu-

tions, containers and packaging: Specifications must be available for all criti-cal equipment and consumables. Consumables and equipment must bequarantined and shown to comply with specifications prior to use with support-ing evidence recorded. Critical equipment must be serviced and maintained toschedule and where appropriate be validated and calibrated for use. All process-ing records must include batch numbers with expiry dates of consumables andequipment logs to demonstrate the kit used, with linkage to sterilisation cycles ifapplicable. Mechanisms must be in place to permit quarantine or recall of tissueexposed to materials subsequently found to be non-conforming.


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AUDIT GUIDANCE:Verify that all equipment is suitable for its purpose, sterilised and validated

and calibrated for use where appropriate, by checking the appropriate documen-tation. Specifications must be available for all critical equipment and consumables.There must be a mechanism for quarantine and recall of tissues exposed to non-conforming materials. Ask for a short demonstration on tracking (where to findthe detailed information, etc.). Processing records must include batch numberswith expiry dates of consumables, and equipment logs to demonstrate the kitused, with linkage to sterilisation cycles if applicable.

CHECKLIST: Sterility, suitability and traceability of instruments,reagents and solutions, containers and packaging.

Is there a procedure for identifying and managing critical supplies? Yes No N/A

1. Specifications will be available for all critical equipment and consumables.Are critical equipment and supplies catalogued? Yes No N/A Does this catalogue encompass all critical equipment and supplies? Yes No N/A Does each item have a requirement/acceptance specification? Yes No N/A

2. Consumables and equipment will be quarantined and shown to comply withspecification prior to use with supporting evidence recorded.Has each item being approved for use against specification? Yes No N/A Is there an effective segregated quarantine area for receipt of goods?

Yes No N/A

3. Critical equipment will be serviced and maintained to schedule and where ap-propriate be validated and calibrated for use.Is there a maintenance/servicing catalogue for all critical equipment?

Yes No N/A Are there signed, current service agreements defining responsibilities and specifications ofwork required? Yes No N/A Is it clear that equipment in use is fit for use? Yes No N/A Is there a mechanism for ensuring that unsuitable equipment is ‘removed’ from use?

Yes No N/A Are validation/calibration records available for critical items? Yes No N/A Are validation/calibration reports approved/accepted by the tissue bank?

Yes No N/A


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4. All processing records will include batch numbers with expiry dates of con-sumables, and equipment logs to demonstrate the kit used with linkage to sterili-sation cycles if applicable.Do processing records include batch numbers and expiry of supplies?

Yes No N/A Do processing records record critical equipment kit used? Yes No N/A

5. Mechanisms must be in place to permit quarantine or recall of tissue exposedto materials subsequently found to be non-conforming.Are materials used checked for suitability and being in date as part of routine quality mon-itoring and tissue release? Yes No N/A Can supplies and equipment be traced in the event of recall? Yes No N/A Is there evidence that a practice or real tracking exercise been undertaken recently basedon a supplies/consumables recall? Yes No N/A Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________

D.3 ENVIRONMENTAL CONTROLS

STANDARD: Processing and storage areas must be kept clean with evidence of cleaning

documented. Tissues exposed to the environment without terminal microbial in-activation must be processed in GMP air quality grade A. Deviation from GMPgrade A above must be specified, validated and justified. Tissues exposed to theenvironment with subsequent terminal sterilisation must be processed at least inEuropean Directive air quality grade D (best if processed in GMP air qualitygrade C). The effectiveness of equipment and cleaning must be validated andmonitored to demonstrate specified limits with no cross contamination. Staffgowning and hygiene must be documented, validated and qualified. Environmentalmonitoring must be reviewed as part of product release. Trends must be analysedand reviewed as part of routine quality review.

AUDIT GUIDANCE:Observe for the presence of unused equipment, too much traffic from unau-

thorised staff, inappropriate storage of reagents and supplies, etc, since these maycontribute to an unsafe environment.

Check the air quality grade used in processing and storage areas.Verify that equipment and cleaning effectiveness is validated and monitored.Check that cleaning of rooms and storage areas is documented.


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CHECKLIST: Environmental Controls

1. Processing and storage areas are kept clean with evidence of cleaning documented.Is there a cleaning policy for controlled and uncontrolled areas? Yes No N/A Is there a cleaning record for all GMP areas? Yes No N/A Are the GMP areas clean and tidy (to enable effective cleaning)? Yes No N/A Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________

2. Tissues exposed to the environment without terminal microbial inactivation willbe processed in GMP air quality grade A.Are non-terminally sterilised tissues processed in grade A? Yes No N/A Where a grade B background is not used, is the grade A validated? Yes No N/A Justification: ______________________________________________________________________________________________________________________________Is there evidence staff are regularly trained in GMP aseptic working?

Yes No N/A Is the processing grade qualified for each batch processed? Yes No N/A Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________

3. Deviation from GMP grade A above must be specified, validated and justified.Is the processing environment reviewed against standard? Yes No N/A Where non-conforming, are tissues segregated to prevent release?

Yes No N/A If released for clinical use, is the rationale documented and independently approved?

Yes No N/A Is clean room/cabinet performance reviewed and are performance trends analysed by thetissue bank and an independent person? Yes No N/A Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________


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4. Tissues exposed to the environment with subsequent terminal sterilisation willbe processed at least in European Directive air quality grade D (best if processedin GMP air quality grade C).Are terminally sterilised tissues processed in air quality grade D? Yes No N/A Are terminally sterilised tissues processed in air quality grade C? Yes No N/A Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________

5. The effectiveness of equipment and cleaning must be validated and monitoredto demonstrate specified limits with no cross contamination.Are cleaning agents validated for purpose including effectiveness? Yes No N/A Is the clean room and/or working cabinet certified for use against relevant standards bya qualified person? Yes No N/A Has practice been independently reviewed to determine risk of contamination and meas-ures taken to mitigate the risk? Yes No N/A Are products tested to ensure they have not been contaminated? Yes No N/A Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________

6. Staff gowning and hygiene must be documented, validated and qualified. Are staff trained in gowning practice? Yes No N/A Is there a staff hygiene policy including attire, makeup etc.? Yes No N/A Are staff regularly assessed for aseptic gowning performance? Yes No N/A Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________

7. Environmental monitoring reviewed as part of product releaseDoes product release include:

- Clean room monitoring includes plates, pressures, particles, etc?Yes No N/A

- Cabinet monitoring? Yes No N/A - Gloveprint monitoring? Yes No N/A - Product contamination monitoring? Yes No N/A

Does non-conformity include a retrospective review of inventory? Yes No N/A Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________


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8. Trends analysed and reviewed as part of routine quality reviewAre deviations recorded as Quality Incidents? Yes No N/A Is there trend analysis data with route cause analysis? Yes No N/A Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________

D.4 TRACEABILITY OF TISSUE THROUGH PROCESSING

STANDARD: Donation data kept must include:

- Tissue establishment or procurement organisation- Unique ID number- Date and place of procurement- Type of donation (allo/auto, living/deceased etc)

Product data kept must include:- Tissue establishment responsible- Type of product- Batch/pool if applicable- Split if applicable- Expiry date- Status (e.g. quarantine/fit for use)- Description of process, materials and additive lot numbers- Date and location of distribution/disposal

AUDIT GUIDANCE:Select four processing reports at random and verify that the donation and

product data stated above is included.

CHECKLIST: Traceability of tissue through processing

1. An effective and accurate system must be defined to ensure unique identificationof tissues throughout the banking process from receipt to distribution.Can tissue be effectively tracked throughout the process? Yes No N/A Does this include what task was performed by whom, and where and when?

Yes No N/A Is a traceable tissue storage inventory kept (current and retrospective)? Yes No N/A Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________


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2. Donation data kept will include as a minimum: - Tissue establishment or procurement organisation Yes No N/A - Unique ID number Yes No N/A - Date and place of procurement Yes No N/A - Type of donation (allo/auto, living/deceased etc) Yes No N/A


3. Product data kept will include as a minimum:- Tissue establishment responsible Yes No N/A - Type of product Yes No N/A - Batch/pool if applicable Yes No N/A - Split if applicable Yes No N/A - Expiry date Yes No N/A - Status (e.g. quarantine/fit for use) Yes No N/A - Description of process, materials and additive lot numbers Yes No N/A - Date and location of distribution/disposal Yes No N/A


D.5 MICROBIOLOGICAL TESTING OF FINAL TISSUE

STANDARD: There must be an evidenced/risk-based release policy on microbiology in-

cluding sampling methodology and exclusion criteria. Tissues not terminally ster-ilised must be sampled just prior to final packaging. Retrieved tissuecross-contamination must be assessed as exclusion criteria. Test results or method-ology must be approved by a microbiologist. There must be a review of microbi-ology results prior to tissue release.

AUDIT GUIDANCE:Verify that there is a record of the microbiological testing of the final tissues,

approved by a microbiologist (select four donor records and search for the mi-crobiology testing results). Verify that tissues not terminally sterilised are sampledjust prior to final packaging.


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CHECKLIST: Microbiological Testing of Final Tissue

1. There will be an evidenced/risk-based release policy on microbiology includingsampling methodology and exclusion criteria:

- Policy in place for release criteria regarding bacterial, fungal and spore contamina-tion of grafts Yes No N/A

- SOPs for sampling Yes No N/A - Risk assessment for methodology used for sampling Yes No N/A

2. Tissues not terminally sterilised will be sampled just prior to final packaging.Sampling occurs at time critical points in the process:

- Pre final packaging for non sterilised grafts Yes No N/A

3. Retrieved tissue cross contamination will be assessed as an exclusion criteria.Sampling occurs at time critical points in the process:

- Pre process Yes No N/A - Pre final packaging for non sterilised grafts Yes No N/A

4. Test results or methodology will be approved by a microbiologist.Process and validation approved by qualified microbiologist Yes No N/A

Accountability is via a registered practitioner in microbiology Yes No N/A

5. Review of microbiology results prior to tissue releaseIs there a review of the microbiology test results before the tissue is released?


D.6 ADVERSE EVENT MANAGEMENT

STANDARD: TE must have a system for the detection, evaluation, documentation and re-

porting of errors and adverse reactions and events. TE must have a system for cor-rective and preventive actions. Corrective actions must be documented, initiatedand completed in a timely and effective manner. Preventive and corrective actionsshould be assessed for effectiveness after implementation.


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AUDIT GUIDANCE:Verify that there is a system in place for the detection, evaluation, documen-

tation and reporting of errors and adverse reactions and events, and for correc-tive and preventive actions. Check that these are effective.

CHECKLIST: Adverse Event Monitoring

Does the TE have a system for the detection, evaluation, documentation and re-porting of errors and adverse events? Yes No N/A Does the TE have a system for corrective and preventive actions?

Yes No N/A Are corrective actions documented, initiated and completed in a timely and effec-tive manner? Yes No N/A Are preventive and corrective actions assessed for effectiveness after implementa-tion?



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PART E: TISSUE STORAGE

E.1 GENERAL PRINCIPLES

STANDARD: Validation of containers and packaging materials: Transport pack-

aging/containers must be validated fit for use, specified and treated as a crit-ical item.

Clear separation between tissues available for distribution and inquarantine: Tissues that are fit for transplant must be clearly segregatedfrom tissues in quarantine. The process flow must not permit mix up be-tween products in different stages of production.

AUDIT GUIDANCE:Select four transport package containers at random and check for

their integrity, quality and function. These containers must be validatedas fit for use, and specified and treated as critical items. Verify that tis-sues fit for transplant are clearly segregated from tissues in quarantine.Check that the process flow does not permit mix up between productsin different stages of production. Confirm that cleaning of storage areasis documented.


1. Validation of containers and packaging materials1.1 Transport packaging/containers must be validated fit for use, specified and treated asa critical item:

- All transport packaging validated fit for purpose Yes No N/A - Control of transport containers as critical products Yes No N/A - Volume of coolants validated and specified in SOPs Yes No N/A

2. Clear separation between tissues available for distribution and in quarantine.2.1 Quarantined and fit for transplant tissues segregated Yes No N/A 2.2 Process flow does not permit mix up between products in different stages of pro-duction. Yes No N/A Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________


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E.2 STORAGE CONDITIONS

STANDARD: There must be a system for the control of relevant physical conditions (e.g.

temperature). There must be continual alarmed temperature monitoring as well asfull audit of inventory against its temperature history. There must be storageequipment validation prior to release into use and following repairs. Temperaturemapping of appliance must be carried out.

AUDIT GUIDANCE:Verify that there is a system for the control of relevant physical conditions (e.g.

temperature, humidity, CO2...). There must be continual alarmed temperaturemonitoring as well as full audit of inventory against its temperature history. Checkthat storage equipment is validated prior to release into use and following repairs.Temperature mapping of appliance must be carried out.

CHECKLIST: Storage Conditions

Control of relevant physical conditions (e.g. temperature):- Continual alarmed temperature monitoring Yes No N/A - Full audit of inventory against its temperature history Yes No N/A - Storage equipment validation prior to release into use and following repairs.

Yes No N/A - Temperature mapping of appliance has been carried out Yes No N/A


E.3 TISSUE RELEASE

STANDARD: There must be a safe system for authorising and executing the transfer of tis-

sues from quarantine to available for distribution. Expiry dates must be estab-lished for all tissues released. Release for transplantation must be done by theresponsible medical officer and quality assurance officer. There must be SOPs forthe release and exceptional release of tissue for transplantation.

AUDIT GUIDANCE:Ask the person responsible for tissue release to show you how the transfer of

tissues in quarantine to available for distribution is made. Verify that expiry dates


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are always established for all tissues released. Ask for and review the SOP of re-lease and exceptional release of tissue for transplantation.

CHECKLIST: Tissue Release

1. Safe system for authorising and executing the transfer of tissues from quaran-tine to available for distribution:

- SOP for release in place Yes No N/A - SOP for transfer to clinical use Yes No N/A - Release includes medical, production and independent quality approval

Yes No N/A - Mechanism for release is approved by the Responsible Person

Yes No N/A

2. Expiry dates established for all tissues released2.1 Expiry date defined:

- Expiry dates are validated to maintain tissues fit for purpose Yes No N/A - Expiry times are defined in policy Yes No N/A

2.2 Stock control:- Inventory is up-to-date Yes No N/A - Stock is rotated to prevent wastage Yes No N/A - Stock control policy in place Yes No N/A - Stock control manages donation activity to maximise use Yes No N/A



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PART F: TISSUE DISTRIBUTION

F.1 GENERAL PRINCIPLES

STANDARD: Critical transport conditions (such as time limit and temperature) must be de-

fined in Quality Manual or SOPs. Procedures for the handling of requests for tis-sues must be in place. There must be a documented system for the handling ofreturned products. The distribution/allocation policy should ensure equitable ac-cess for recipients. “Clients” should be able to receive products and temporarilystore them under adequate conditions.

AUDIT GUIDANCE:Verify that critical transport conditions (such as time limit and temperature) are

defined in the Quality Manual or in SOPs. Review the documented system for thehandling of requests for tissues and for the handling of returned products. Check thedistribution/allocation policy and verify that it ensures equitable access for recipients.


Are critical transport conditions, such as temperature and time limit, described in SOPs?Yes No N/A

Are procedures for the handling of requests for tissues in place?Yes No N/A

Is there a documented system for the handling of returned products?Yes No N/A

Does the distribution/allocation policy ensure equitable access to tissues for recipients?Yes No N/A

Are internal “clients” able to receive and temporarily store tissues under adequate conditions(different wards of the same hospital where the TE operates)? Yes No N/A Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________

F.2 TRANSPORTATION

STANDARD: Transportation conditions must be defined, assured and validated.The TE should have selected professional transporters who fulfil this criteria;

contract must be present (unless the TE transports the tissues themselves).


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Transport Company should be able to prove that contracted conditions are ade-quately applied. Documented agreement between TE and contracted party mustbe present, to ensure that the required conditions are maintained. TransportCompany must be able to comply with traceability criteria.

AUDIT GUIDANCE:Review contracts between TE and contracted transporters (if applicable) and

the transport conditions agreed. The TE must certify that the transport companyproves that the contracted conditions are adequately applied and these correspondwith traceability criteria.

CHECKLIST: Transportation

Does the TE have selected professional transporters? Yes No N/A Unless the TE transports tissues itself, does it keep contracts of the professional trans-porters? Yes No N/A Is the transport company able to prove that contracted conditions are adequately applied?

Yes No N/A Is there documented agreement between the TE and the contracted party?

Yes No N/A Does the transport company comply with traceability criteria? Yes No N/A Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________

F.3 RECEPTION POLICIES AT THE END USER

STANDARD: The end user should be instructed beforehand about the time, nature and

handling of the transported package.Users applying tissues must be required to store data on:

- Supplying establishment- End user and facility- Product type and identifier- Recipient identifier - Date of use/disposal

AUDIT GUIDANCE:If at the time of the on-site audit there are packages which are shortly to

be sent to end users, confirm that they contain instructions about the nature


80


and handling of the package. The TE must ensure the end user stores the datalisted above.

CHECKLIST: Reception Policies at End User

Does the TE instruct the end user (before the reception of the package) about thetime/nature and handling of the transported package? Yes No N/A Users applying tissues will be required to store data on:

- Supplying establishment Yes No N/A - End user and facility Yes No N/A - Product type and identifier Yes No N/A - Recipient identifier Yes No N/A - Date of use/disposal Yes No N/A


F.4 ADVERSE EVENT/REACTION MONITORING ANDRECALL

STANDARD: The management of Serious Adverse Reactions/Events and non-conformi-

ties (system of vigilance) must be suitable and contained in SOPs. There must bepersonnel authorised within the TE to assess the need for recall and to initiateand coordinate necessary actions. An effective recall procedure must be in place,including a description of the responsibilities and actions to be taken, in order tonotify the TE without delay of any SAR/E that may influence the quality andsafety of tissues.

The TE shall provide the organisation responsible for human application withinformation about how the organisation should report SAR/E (which may influ-ence the quality and safety of tissues) to them.

TE must have procedures in place to communicate all relevant available in-formation about suspected SAR/E to the competent authority without delay, aswell as the conclusions of the investigations to analyse the cause and the ensuingoutcome. See annexes III and IV of Directive 2006/86/EC for notification ofSAR/E to competent authorities. Actions must be taken within pre-defined peri-ods of time.


81


AUDIT GUIDANCE:Confirm that there is a suitable system of vigilance and that it is described in

SOPs. Verify that there is an effective recall procedure in place, which includes adescription of the responsibilities and actions to be taken.

Check that the TE provides the organisation responsible for human applica-tion with information on how to report SAR/E to them.

Confirm that there is a system in place for the communication of SAR/E andtheir outcomes to the Competent Authority in the country.

CHECKLIST: Adverse Event Monitoring and Recall

Is the management of Serious Adverse Reactions/Events and non-conformities (systemof vigilance) suitable and described in SOPs? Yes No N/A Is there an effective recall procedure? Yes No N/A

Are there personnel authorised in the TE to assess the need for recall and to initiate andcoordinate necessary actions? Yes No N/A Does the recall procedure include a description of the responsibilities and actions to betaken (notify the TE without delay of any SAR/E which may influence the quality andsafety of tissues)? Yes No N/A Does the TE provide the organisation responsible for human application with informa-tion about how to report SAR/E to them? Yes No N/A Does the TE have procedures in place to notify the competent authority without delayabout suspected SAR/E? Yes No N/A Does it also communicate all the conclusions of the investigations? Yes No N/A Are actions taken within pre-defined periods of time? Yes No N/A Auditor Comments: ______________________________________________________________________________________________________________________________________________________________________________________________

F.5 WAITING LISTS AND IMPORT/EXPORT POLICIES

STANDARD: Waiting lists for recipients of each tissue must ensure fair allocation for each

recipient. The following criteria may be observed:- Medical urgency- HLA match- Paediatric recipients- Physical characteristics of the available graft and the requested trans-

plant criteria for the recipient


82


- Country/region of origin of recipient and donor- Waiting time

Import and export policies: Member States must take all necessary measures to ensure that import and ex-

port of tissues/cells is done by TEs accredited, designated, authorised or licensedfor the purpose of those activities, always ensuring traceability.

Member states and TEs which import and export tissues and cells from/tothird countries must guarantee that they meet the standards of quality and safetyequivalent to those laid down in European Directive 2004/23/EC, or have the na-tional authority’s permit to import from non-conforming sources.

AUDIT GUIDANCE:Check the distribution/allocation policy and verify that, for each tissue, fair al-

location for each recipient is ensured. The TE must ensure that the entities from/to which it imports/exports are

accredited, designated, authorised or licensed for the purpose of those activities(by the country of origin). Verify that the TE also guarantees that these centresfrom third countries meet the standards of quality and safety equivalent to thoseshown in European Directive 2004/23/EC (set out in this Guide).

CHECKLIST: Waiting Lists and Import/Export Policies

Do waiting lists for recipients of each tissue ensure fair allocation for each recipient?Yes No N/A

Is the following criteria observed?- Medical urgency Yes No N/A - HLA match Yes No N/A - Paediatric recipients Yes No N/A - Physical characteristics of the available graft and the requested transplant criteria for

the recipient Yes No N/A - Country/region of origin of recipient and donor Yes No N/A - Waiting time Yes No N/A



83

6 . SHORTCU T TO AUDI T GUIDA NCE

(PA RT S A TO F)

PART A: GENERAL POLICIES

A.0 GENERAL CONSIDERATIONS FOR AUDITORS· Communicate with establishment to be audited ahead of time about:

agenda, identity of auditor(s), procedure, estimated duration of theaudit.

· Request for the TE’s Site Master File (see Annex 2) duly completed somedays before the audit.

· Explain the nature and the scope of the audit in writing.· Arrange confidentiality of the auditors.· Ask for certificates and/or copies of audit reports from other auditors.· Communicate with each other to prepare the audit some days before

travelling to the institution to be audited.

A.1 LEGAL AND REGULATORY FRAMEWORK Check presence of copies of the European Directives and the applicable law(s).Review the organisational chart and Quality System manual, and look for references

to laws and regulations.

A.2 STANDARD OPERATING PROCEDURES (SOPs)The TE must provide the audit team with a table of contents of the SOP Manual,

since there will not be time to read the entire manual during the on-site audit. This tableof contents should be examined for evidence of SOPs addressing each item (listed onpage 26) before arriving at the audit site. Select one SOP at random and verify that the ma-


84

s h o r t c u t t o a u d i t g u i d a n c e

terial, equipment and personnel involved are identified. Review the document control pro-cedure. Verify that only the current version of the SOP is in use.

A.3 SPECIFIC ASPECTS OF THE QUALITY SYSTEMAsk the responsible person to show you the Quality system manual, the list of SOPs

(and one random procedure), training manuals, a donor record, written agreements be-tween TE and contracted parties, the internal and external auditing system in place, the sys-tem for detecting non-conformities, notifying SAE/Rs and proof of preventive andcorrective actions.

A.4 DATA PROTECTION AND ANONYMITYVerify that donor and recipient information remains unidentifiable in data available to

third parties. Check that unauthorised personnel do not have access to any information thatrequires it. Check for password renewal management. Beware of uncontrolled passwordson PCs, on post-its, etc.

A.5 TRACEABILITYReview adverse event and recall procedures (see section F.6).Review four donor records at random and verify that traceability is ensured. For com-

puter systems, perform a trial: check how tissue allocation is performed and what the cri-teria are.

Select one finished released tissue at random and ask staff to show you how they canfind the associated donor record, which lots and batches of reagents were used in the pro-cessing, where it is documented that the tissue was released for distribution and by whom,etc.

A.6 PERSONNEL TRAINING AND QUALIFICATIONMeet with the person in charge of hiring new personnel and check how the procedure

is carried out. Check training and retraining system and instruction procedure. Select threepersonnel files at random and check that on-the-job training and competence is docu-mented, and up-to-date job descriptions, educational history and diplomas are included forpersonnel.

A.7 HEALTH & SAFETY OF STAFF; COMPLIANCE WITHLEGAL REQUIREMENTS

Identify the facility personnel responsible for these activities. If possible, auditorsshould observe personnel for use of protective clothing and biosafety precautions.Observe caution signage and nitrogen storage monitoring and control. Examine a fewemployee files at random for compliance and training in radiation, biological and chemi-cal safety, as well as risk assessment. Review documentation to check whether there is a


85


procedure for accidental cuts during procurement or processing, as well as for the subse-quent testing and treatment of the staff member who has been cut or otherwise been incontact with donor blood during the procurement or processing.

A.8 PACKAGING AND LABELLINGVerify that labels and labelling are in accordance with the corresponding SOP. Observe

where labels are stored and verify that they are organised in a way that prevents errors.Select four package containers at random and check their integrity, quality and function.Check that labelling is resistant to water and that it shows essential information, includingphrases such as “dry ice”, “this side up”, “handle with care”, “human tissue for trans-plantation” and/or “biohazard” if applicable. Verify that the labels in use meet the re-quirements listed in Table 1 (page 37).

Confirm that labels:· Are correctly fixated to the package (and/or tag)· Are positioned properly· Are identical to the ones in SOP· Are legible and accurate· Have unique identification code firmly fixated to the product package, and that

this code is identical to the one in the TE’s associated forms· Are not damaged or spoilt· In which there is hand written data, it is done so with permanent ink

A.9 RECORDS AND REGISTERSVerify that the record keeping system is documented and includes at least the

following:· Location of new and completed forms· Method of error correction· Method to prevent destruction or loss of the record· Method of documenting modifications and distribution· Time of retention and proper storage location· System to ensure confidentiality of records· Methods for filing and transfer of records to archival storage

With regard to donor files, be alert to breaches in policy that potentially compromisedonor confidentiality (unsecured patient records; patient charts left unattended in areaswhere restricted personnel and/or visitors may have access, or unattended computerscreens displaying patient information in these areas; patient information posted on bul-letin boards which are potentially visible by non-medical staff; release of confidential in-formation without appropriate consent; etc.). Check that release for transplantation isdone by responsible medical officer and quality assurance officer.


86


With regard to recipient archives, select four of them at random and verify that theinformation stated in this standard is included (page 41).

PART B: TISSUE DONATION

B.1 DONOR SELECTION AND EVALUATIONVerify that a face-to-face interview is conducted with living donors by speaking to the

person in charge and by examining the questionnaire completed during the interview. Fordeceased donors, review the sources of information used.

Donor identity: Review identification procedure and by whom it is carried out.Donor consent details: Authorised person who confirms and records that the consent

has been obtained in accordance with the legislation in place in the Member State. Check thatall consents required by local regulations and legislation are obtained. For living donor, ver-ify that the informed consent includes notification of all reasonable risks and potential harm,as well as tests to be performed. Verify that the request for donation is explained in under-standable terms by a health care professional familiar with the donation process.

Medical history requirements/ Assessment of behavioural risks/ Physical ex-amination forms: Review Medical History form to confirm that adequate information issought to allow the application of the exclusion criteria in Technical Annex 1 of Directive2006/17/EC (listed on ‘medical history requirements’ checklist on page 46). Select fourdonor records at random to examine the evidence that all the exclusion criteria have beenappropriately investigated and applied. Check that information regarding the donor’s be-havioural history (increasing the risk of transmissible diseases) is explored. Physical ex-amination forms: verify that key points are always answered (never blank), and if answered“yes”, an explanation is given. Verify that any signs that may be sufficient in themselvesto exclude the donor are detected, giving special attention to tumours, infections, risk fac-tors for transmissible diseases, traumas to the donor’s body and scars from recent or oldoperations.

Assessment of testing results: Check that the notification of confirmed positivetest results is carried out.

B.2 DONOR CODING Review the donor coding system in place at the TE and check that the following in-

formation is incorporated: unique ID number, identification of the TE.

B.3 DONOR TESTINGVerify that serological tests required for the donors include: Anti HIV 1 and 2, HBsAg,

Anti HBc, Anti HCVAb and testing for syphilis. Check that blood samples are obtainedas a maximum twenty-four hours after death for cadaveric donors, and seven days post do-nation for living donors unless it is possible to obtain it at the time of donation.


87


Verify that appropriate investigations are carried out to ensure that blood samplesused for testing are not diluted by prior transfusions or infusions so as to render the testresult invalid.

B.4 DONOR DOCUMENTATIONSelect four donor records at random to examine that all the information stated below

is explored and recorded. Verify that for all this criteria, the person responsible is given: · Donor identification· Age· Sex· Cause of death (time and circumstances also recommended)· Medical and social history· Relevant clinical data· Consent form· Body examination results· Procurement report· Haemodilution formula· Laboratory and other test results· Autopsy/biopsy results, if applicable

PART C: TISSUE PROCUREMENT

C.1 GENERAL PRINCIPLESReview the donor and product coding system in place at the TE and check that the

following information is incorporated: unique ID number, identification of the TE, product code,split number and expiry date.

Speak with person responsible for donor identification before procurement and askfor explanation of how donor is identified.

Verify in the procurement report / donor file that consent for tissue retrieval is ob-tained by the responsible person.

C.2 RETRIEVAL CONDITIONSPersonnel and Facilities: Select four procurement personnel profiles and check qual-

ification of workers. Meet personnel and visit procurement rooms, if feasible. Verify thatpersonnel clothing and hygiene are adequate.

Equipment: Check lot number and expiry date of sets of equipment, reagents andmediums. Check quality and sterility of equipment.

Retrieval Techniques and Prevention of Contamination: During clean, non-ster-ile procurement, check sterilising methods used and their validation.

Microbiological Testing of Tissues Retrieved: Check the identification of samples


88


taken. Verify that the date of sampling is recorded. (Recording time of beginning and endof retrieval is important, as sampling is routinely done during retrieval, before packagingthe tissue.). For live donations (surgical residues) it is enough to be able to track down thetime of the operation.

C.3 RETRIEVAL DOCUMENTATIONSelect four procurement reports and verify that the following information is observed:

· Donor identity· Date, time and place of the procedure· Identity of the person (s) performing the retrieval· Tissue(s) retrieved· Donor and tissue selection information· Details of the physical examination of the donor prior to retrieval· Autopsy report, if applicable· Name (in capitals) of the responsible procurement officer

These reports must be completed and signed by designated procurement team mem-bers and checked and signed by a responsible person, or his/her assignee, and maintainedfor at least thirty years.

C.4 TRANSPORTATION TO TECheck for the presence of written procedures which verify that transport conditions

are validated and provided under conditions which minimise the risk of contamination andguarantee the retaining of the original biological properties of the tissues procured.Examine a few packaging containers and their labels and check for their suitability andwhether the safety of the products is maintained.

PART D : TISSUE PROCESSING

D.1 GENERAL PRINCIPLESVerify that there are SOPs for tissue processing. Select two staff training records at ran-

dom and review that staff have continuing competence and compliance with SOPs. Reviewthe coding system. Select two processing reports at random and verify that they includethe following data: unique ID number, identification of the tissue establishment, product code,pack/split number if applicable, and expiry date.

Verify that all the methods applied are validated and that processing procedures aresafe for the tissue and staff. Verify that there are written procedures for the control ofcross-contamination, as well as for the control and recording of key parameters. Theremust be a procedure to separate quarantine tissue from “approved” tissue.


89


D.2 EQUIPMENT SUITABILITY, STERILITY ANDTRACEABILITY

Verify that all equipment is suitable for its purpose, sterilised and validated and cali-brated for use where appropriate, by checking the appropriate documentation.Specifications must be available for all critical equipment and consumables. There must bea mechanism for quarantine and recall of tissues exposed to non-conforming materials.Ask for a short demonstration on tracking (where to find the detailed information, etc.).Processing records must include batch numbers with expiry dates of consumables, andequipment logs to demonstrate the kit used, with linkage to sterilisation cycles if applica-ble.

D.3 ENVIRONMENTAL CONTROLSObserve for the presence of unused equipment, too much traffic from unauthorised

staff, inappropriate storage of reagents and supplies, etc, since these may contribute to anunsafe environment.

Check the air quality grade used in processing and storage areas: Tissues exposed to theenvironment without terminal microbial inactivation must be processed in GMP air qual-ity grade A. Deviation from GMP grade A above must be specified, validated and justified.If there is terminal sterilisation of tissues, processing must take place at least in EuropeanDirective air quality grade D (although best if processed in GMP air quality grade C).

Verify that equipment and cleaning effectiveness is validated and monitored.Check that cleaning of rooms and storage areas is documented.

D.4 TRACEABILITY OF TISSUE THROUGH PROCESSINGSelect four processing reports at random and verify that the donation and product

data stated below is included. Donation data:

· Tissue establishment or procurement organisation· Unique ID number· Date and place of procurement· Type of donation (allo/auto, living/deceased etc)

Product data:· Tissue establishment responsible· Type of product· Batch/pool if applicable· Split if applicable· Expiry date· Status (e.g. quarantine/fit for use)· Description of process, materials and additive lot numbers· Date and location of distribution/disposal


90


D.5 MICROBIOLOGICAL TESTING OF FINAL TISSUEVerify that there is a record of the microbiological testing of the final tissues, ap-

proved by a microbiologist (select four donor records and search for the microbiologytesting results). Verify that tissues not terminally sterilised are sampled just prior to finalpackaging.

D.6 ADVERSE EVENT MANAGEMENTVerify that there is a system in place for the detection, evaluation, documentation and

reporting of errors and adverse reactions and events, and for corrective and preventive ac-tions. Check that these are effective.

PART E: TISSUE STORAGE

E.1 GENERAL PRINCIPLESSelect four transport package containers at random and check for their integrity, quality

and function. These containers must be validated as fit for use, and specified and treated ascritical items. Verify that tissues fit for transplant are clearly segregated from tissuesin quarantine. Check that the process flow does not permit mix up between productsin different stages of production. Confirm that cleaning of storage areas is documented.

E.2 STORAGE CONDITIONSVerify that there is a system for the control of relevant physical conditions (e.g. tem-

perature, humidity, CO2...). There must be continual alarmed temperature monitoring aswell as full audit of inventory against its temperature history. Check that storage equipmentis validated prior to release into use and following repairs. Temperature mapping of ap-pliance must be carried out.

E.3 TISSUE RELEASEAsk the person responsible for tissue release to show you how the transfer of tissues

in ‘quarantine’ to ‘available for distribution’ is made. Verify that expiry dates are alwaysrecorded for all tissues released. Ask for and review the SOP of release and exceptionalrelease of tissue for transplantation.

PART F: TISSUE DISTRIBUTION

F.1 GENERAL PRINCIPLESVerify that critical transport conditions (such as time limit and temperature) are defined

in the Quality Manual or in SOPs. Review the documented system for the handling of re-quests for tissues and for the handling of returned products. Check the distribution/allo-cation policy and verify that it ensures equitable access for recipients.


91


F.2 TRANSPORTATION

Review contracts between TE and contracted transporters (if applicable) and thetransport conditions agreed. The TE must certify that the transport company proves thatthe contracted conditions are adequately applied and they comply with traceability crite-ria.

F.3 RECEPTION POLICIES AT THE END USERIf at the time of the on-site audit there are packages that will shortly be sent to end

users, confirm that they contain instructions about the nature and handling of the pack-age. Verify that the TE ensures the end user stores the data listed below:

· Supplying establishment· End user and facility· Product type and identifier· Recipient identifier· Date of use/disposal

F.4 ADVERSE EVENT/REACTION MONITORING ANDRECALL

Confirm that there is a suitable system of vigilance and that it is described in SOPs.Verify that there is an effective recall procedure in place, which includes a description ofthe responsibilities and actions to be taken.

Check that the TE provides the organisation responsible for human application withinformation on how to report SAR/E to them.

Confirm that there is a system in place for the communication of SAR/E and theiroutcomes to the Competent Authority in the country.

F.5 WAITING LISTS AND IMPORT/EXPORT POLICIESCheck the distribution/allocation policy and verify that, for each tissue, fair allocation

for each recipient is ensured. The TE must ensure that the entities from/to which it imports/exports are accred-

ited, designated, authorised or licensed for the purpose of those activities (by the countryof origin). Verify that the TE also guarantees that these centres from third countries meetthe standards of quality and safety equivalent to those shown in European Directive2004/23/EC (set out in this Guide).



93

7 . Audi t Rep or t


94

a u d i t r e p o r t

AUDIT REPORT FORM

DATE:

AUDITED ORGANISATION

Name:

Address:

Location:

Representative:

AUDITEES

NAME:

DEPARTMENT/ ESPONSIBILITY

AUDITORS

NAME:

ENTITY / RESPONSIBILITY:


95


OOBJECTIVES AND SCOPE OF THE AUDIT


96


SSUMMARY OF REPORT

11. PARTS AUDITED

ELEMENT Parts

audited

NC

Quality management system, Quality strategy � �

Documentation requirements – (quality manual, SOPs, guidelines, records)

� �

Management commitment � �

Customer focus � �

Quality policy � �

Responsibilities, authority and communication � �

Quality management review � �

Personnel competency and training � �

Infrastructure � �

Supporting services and agreements � �

Data protection and anonymity � �

PProduct r eal izat ion –– genera l concepts

Identification and traceability � �

Validation of processes � �

Equipment suitability � �

Environmental conditions of production area � �

Pooling and cross-contamination � �

Control of monitoring and measuring devices – calibration, …

� �

Packaging and labelling of product � �

TTissue Donation

Donor coding � �

Donor selection and evaluation � �

Donor documentation � �

Donor testing � �

TTissue Procurement

Method and conditions � �

Retrieval documentation � �

Transport to processing centre � �

TTissue Processing

Processing conditions � �

Microbiological testing of final tissue � �

TTissue Preservation and Storage

Conditions � �

Quarantine � �

Tissue release – authority… � �

TTissue Distr ibution

Transportation � �

Reception policies at end user � �

Waiting lists � �

Import/Export policies

� �


97


MMeasurement,, analysi s and improvement

Customer satisfaction � �

Internal audits � �

Monitoring and measurement of processes � �

SAR/E management and product recall system � �

Analysis of data � �

Continual improvement � �

Corrective actions � �

Preventive actions � �

22. DOCUMENTATION REVIEWED

DOCUMENTS YYES NNO NNot avai lab le

Quality Manual � � �

SOPs � � �

Guidelines, if any � � �

Annual report � � �

Previous audit reports, if any � � �

Donor records � � �

Records on tissue procurement and processing � � �

Records on tissue distribution � � �

Equipment records � � �

Site Master File completed � � �

AAddit ional Comments


98


CCRITICAL NON--CCONFORMITIES

11.

22.

33.

MMAJOR NON--CCONFORMITIES


99


MMINOR NON--CCONFORMMITIES

OBSERVATIONS


100


AAUDIT SUMMARY

SSTRONG POINTS

TTIMESCALE FOR CORRECTIVE ACTIONS


101


SSIGNATURE OF AUDITORS

NName

SSignature



103

8 . A nnexe s


104

a n n e x e s

Annex 1. Information on the minimum donor/recipient dataset to be kept as required in Article 9 (Annex VI of EUDirective 2006/86/EC)

A. BY TISSUE ESTABLISHMENTS

· Donor identification· Donation identification which should 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 allogeneic; living v de-

ceased)· Product identification which should 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 theirquality and/or safety

- Identification of the facility issuing the final label· Human application identification which should include at least:

- Date of distribution/disposal- Identification of the clinician or end user/facility

B. BY ORGANISATIONS RESPONSIBLE FOR HUMAN APPLICATION

· Identification of the supplying tissue establishment· Identification of the clinician or end user/facility· Type of tissues and cells· Product identification· Identification of the recipient· Date of application


105

a n n e x e s

Annex 2. Site Master File

SSITE MASTERFILE

Table of Contents

Section

Titl e Page

1

General Information

2

Personnel

3

Premises and Equipment

4

Documenta tion

5

Processing

6

Quali ty Control

7

Contract Manufacture and Analysi s

8

Distribution, Complaints and Product Recal l

9

Inspection and Audi t

Appendix 1

Reporting l ines

Appendix 2

Roles and Responsibi l i ti es as described by the EUTCD

Appendix 3 Building plans TE

104

106

108

109

109

109

110

110

110


106

a n n e x e s

1 GENERAL INFORMATION

1.1 Tissue Establishment name, address, contact details and relationship with

parent organisation (if applicable):

1.2 Licensed activities under EUTCD:

1.3 Other manufacturing activities on site:

1.4 Relationship with parent organisation (if applicable):

Company name:

Address:

Telephone:

Relationship:

1.5 Number of donations and types/quantities of tissues/cells produced:

1.6 Site(s) description (where sited and accommodation):

1.7 Number of employees engaged in tissue collection, donor selection, production,

quality assurance, storage and distribution:


107

a n n e x e s

1.8 AActivi ti es contracted out to thi rd par ti es

1.9 QQuali ty management system

Quality Policy Statement:

The mandatory and agreed tissue banking standards applied are:

Responsibi l i ti es of the Qual i ty Function:

Elements of the Qual i ty System/Quali ty Manual :


108

a n n e x e s

2 PERSONNEL

2.1 Organisational chart showing reporting lines for NBSTS and Quality

See Appendix 1 for organisational chart.

See Appendix 2 for clarification of the roles and responsibilities.

2.2 Qualifications, experience and responsibilities of key personnel:

2.2.1 Responsible Person

Name:

Position:

Qualifications:

Relevant experience:

Local responsibilities:

2.2.2 Medical/Clinical

Name:

Position:

Qualifications:



2.2.3 Production

Name:

Position:

Qualifications:



2.2.4 Other (define additional key personnel as required)

Name:

Position:

Qualifications:


Local responsibilities: .


109

a n n e x e s

2.3 TTraining system and method of recording and assuring competency:

2.4 HHeal th requirements for staff

2.5 PPersonal hygi ene/protective clothing requi rements


110

a n n e x e s

33 PREMISES AND EQUIPMENT

3.1 PPremises

See attached site plan/room layout in Appendix 3.

3.2 AAir qual i ty systems for processing/storage laborator ies

3.3 IIn-house manufacture of solutions e .g. di s ti l l ed ster i le water

3.4 MMaintenance (planned preventive maintenance programmes and recording system)

3.5 EEquipment used in the processing and s torage of ti ssue/cel l products :

3.6 MMaintenance/servicing control s/contracts

3.7 VValidation and cal ibra tion system/contracts

3.8 SSof tware used affecting qual i ty ti ssue/cel l s and how control led (acces s and val ida tion) .

3.9 LLabora tory/equipment cl eaning


111

a n n e x e s

4 DOCUMENTATION

4.1 Preparation, revision and distribution of Quality System documentation:

4.2 Other documentation related to product quality:

5 PROCESSING

5.1 Tissue processing overview:

5.2 Starting and packaging materials:

5.3 Arrangements for the handling of rejected materials and products:

5.4 How processes are validated:

6 QUALITY CONTROL

6.1 Quality Control Activities:


112

a n n e x e s

77 CONTRACT MANUFACTURE AND ANALYSIS

7.1 NName and addresses of si tes where processes subcontracted e .g . tissue/equipment steri l isation.

8 DISTRIBUTION, COMPLAINTS AND PRODUCTS RECALL

8.1 SStorage requi rements

8.2 DDistribution process and control including export/import a rrangements

8.3 AArrangements for the handl ing of complaints , product recal l s and

adverse event procedure

Complaints investigation

Product recal l

Adverse event reporting

9 INSPECTION AND AUDIT

9.1 Internal

9.2 External


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a n n e x e s

CCompleted by

Signature: ..................................................................

Title:………………………………………………………..

Date: ..............................................

Appendix 1 – S taff st ructure

Type name here

Type title here

Type name here

Type title here

Type name here

Type title here

Type name here

Type title here

(or attach)

Appendix 2 - Roles and responsibi l i ti es as described by the EUTCD

(Attach here.)

Appendix 3 - Bui lding Plans for Tissue Establ i shment

(Attach here)

Type name hereType title here






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