ISBT Science Series (2007) 2, 143149

ORIGINAL PAPER
Blackwell Publishing Ltd

3A-S10-2

2007 The Authors. Journal compilation 2007 Blackwell Publishing Ltd.

European best practice in blood transfusion: improvement of quality-related processes in blood establishments
Christian Seidl1, Marie OConnell2, Frances Delayney3, Angus McMillan Douglas4, Martin Gorham4, Petra van Krimpen5, Magdalena Letowska6, Leslie Sobaga7, Jeroen de Wit5 & Erhard Seifried1 on behalf of the Projects participants8
1 2

DRK BSDBH, Germany IBTS, Ireland 3 FMD, Luxemburg 4 NBS, United Kingdom 5 Sanquin, The Netherlands 6 IHBP, Poland 7 EFS, France 8 HBRK, Belgium; NBT, Bulgaria; MOH, Cyprus; VFN, Czech Republic; EBS, Estonia HNBT, Hungary; BTS, Iceland; ISS, Italy; IBT, Malta; FMP, Romania; SNBTS, United Kingdom

Transfusion medicine is an expanding eld comprising the interaction between several medical disciplines. Looking at the vein to vein process covering the donation of blood by the voluntary donor up to the application of blood components to patients, modern blood transfusion services comprise a large variety of sociomedical functions. The production of standard cellular blood components, such as erythrocyte and thrombocyte concentrates, plasmatic blood components as well as special cellular components such as blood stem cells, mesenchymal cells or granulocytes will require an extensive laboratory testing repertoire to monitor product quality and safety. The European blood legislation has dened several key quality elements to achieve good manufacturing practice in the eld of blood transfusion. In addition, GMP/GLP and ISO standards are used inter alia by blood establishments. Following the call for proposal in the eld of public health by the European Commission, a consortium of blood establishments from 16 European member, acceding and EFTA states has been established in order to survey the individual quality management systems used by the participants and to developed guidelines for quality systems. These guidelines are aimed at assisting blood establishments in preparing for government inspections as required by Directive 2002/98/EC. They could also be used to adapt existing procedures to comply with current EU requirements and/or to prepare for accreditation and certication of these institutions. Major benets from those quality management systems are (1) the denition of an overall quality policy, (2) improved personnel responsibility, qualication and training, (3) error and risk assessment system, (4) continuous improvement, (5) improved resource management, (6) performance improvement. The denition of costbenet relation between certication and accreditation of blood establishments will depend on the individual institution itself and the amount of processes covered. With the release of the new EU Directive 2005/62/EC, there are currently EU requirements available that describe in detail relevant processes to be covered by quality system following good practice used in blood establishments. A future challenge for transfusion medicine would be optimizing the synergetic effects expressed by the EU directive, GMP and ISO standards. Key words: accreditation, Blood establishment, certication, directive, GMP, ISO, quality.

Correspondence: Prof Dr med. Christian Seidl, MD, European Project Management Section, Department Director, Institute of Transfusion Medicine and Immunohematology, Red Cross Blood Donor Service Baden-Wrttemberg Hessen, Sandhof Strasse 1, 60528 Frankfurt am Main, Germany E-mail: cseidl@blutspende.de The EU-Q-Blood-SOP Project is co-funded by the European Commission Directorate C, Public health program on quality and safety of blood, Project Grant Agreement n0 2004217.

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Fig. 1 This gure shows the relevant areas in blood collecting, processing, testing of blood components and transfusion processes for patients. The project would cover in its reduced form the areas blood donation (donor), donor testing laboratory, blood component production and quality control. The implementation of a quality management system based on GMP and a quality management using ISO 9000 priciples would result in professional excellence and blood safety.

Introduction
Transfusion medicine is an expanding eld comprising the interaction between several medical disciplines. Looking at the vein to vein process covering the blood donation by the voluntary donor up to the application of blood components to patients, modern blood transfusion services comprise a large variety of socio-medical functions. These are dened by the ultimate goal to produce safe blood components with consistent quality for haemotherapy, derived from individual blood donations. The production of standard cellular blood components, such as erythrocyte and thrombocyte concentrates, plasmatic blood components as well as special cellular components such as blood stem cells, mesenchymal cells or granulocytes will require an extensive laboratory testing repertoire to monitor product quality and safety. This will include, for example the testing of blood donations for standard infection markers such as HIV, HCV and HBV by serological and molecular techniques, the denition of cell quality and content of stem cell concentrates by immunophenotyping using ow cytometry and/or cell culture (e.g. stem cell assay) or the haemostaseologic activity of clotting factors in fresh frozen plasma. The optimal therapeutic use of these blood components is accompanied by a close interdisciplinary interaction between the blood transfusion service and the hospital units. In those cases where the blood transfusion service is part of the hospital, this medical interaction will lead to therapeutic councils combined with treatment rounds. If the transfusion service and the hospital or outpatient department are separated, there will be additional impact for the importance of clinical information transferred via documents. In addition, besides the collection, testing and production of blood components, blood establishments will be linked to the diagnostic procedures of patient care.

Taking all the previously mentioned into account, modern blood establishments will comprise complex interactions to cover the transfusion supply (Fig. 1). Regulations and guidelines to cover quality aspect in these processes have been based on good manufacturing practice (GMP) and good laboratory practice (GLP) standards. In addition, ISO9001 and ISO15189 norms developed by the International Organization for Standardization (ISO) have dened quality standards that can be used to dene how an organization should manage or systematize its processes or activities to ensure best practice. These standards and guidelines have been used differently in blood establishments depending on the national legal requirements and or guidelines. In 2002, the European Union established a legislative foundation for setting a high level of quality and safety of human blood and blood components with the adoption of Directive 2002/98/EC [1]. This was followed in 2004 and 2005 by three European Commission Directives setting out the technical implementing measures for issues that are identied in that Directive. The rst deals with certain technical requirements for blood and blood components (2004/33/EC [2]), the second with traceability and the notication of serious adverse reactions and events (2005/61/EC [3]) and the third with standards and specications related to a quality system for blood establishments in the European Union (2005/62/EC [4]). Directive 2002/98/EC places a major obligation on member states and their identied competent authorities to carry out regular inspections and control of all blood establishments on their territory (Article 8). In addition, it requires all blood establishments to establish and maintain a quality system based on the principles of good practice (Article 11). Recognizing this obligation on blood establishments to implement quality systems, the European Commission in its 2004 work plan included as one of its priority actions to support the development and implementation of quality

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management programmes to improve the safety of blood donations to be carried out in the community [5]. The subsequent Call for Proposals [6] specied inter alia that in the area of blood, priority would be given to the development of tools that would provide practical guidance on how to install and maintain quality systems in blood establishments in the member states (Section 224). In response to this call, a consortium of 16 blood establishments with considerable expertise in quality management systems was brought together coordinated by the Red Cross Blood Donor Service (Deutsches Rotes Kreuz Blutspendedienst) of Baden-Wrttemberg in Germany. This consortium involves blood establishments in EU members, acceding or European Free Trade Association (EFTA) countries from Belgium (BE), the Czech Republic (CZ), the Federal Republic of Germany (DE), Estonia (EE), France (FR), the Republic of Ireland (IE), Italy (IT), Cyprus (CY), Hungary (HU), Malta (MT), the Netherlands (NL), Poland (PL), the United Kingdom (UK), Iceland (IS), Bulgaria (BG) and Romania (RO). The consortium, fully aware of the importance of quality management systems in blood services, has established a project-platform (EU-Q-Blood-SOP) on the implementation of good practice by developing a common format and regulations for standard operating procedures (SOPs) to carry out an activity in order to demonstrate compliance with procedures.

Project objectives
The specic objectives of the EU-Blood-SOP project were to: (1) assess the existence of SOP manuals and guidelines currently used in the 16 blood services involved in the project in order to identify (a) international and national SOP manuals already in place and (b) the current inspection practice; (2) develop a manual to assist blood establishments in developing and implementing their own SOPs; (3) test this new SOP methodology among the partner institutions; (4) distribute this manual to (a) the participating blood establishments and (b) to disseminate the results to any interested blood establishments throughout the European Union, acceding or EFTA states using the participating blood establishments as national contact points.

identied and managed. The awareness of inspections as required by Directive 2002/98/EC where relevant was also solicited. Based on the results of the questionnaire, differences and commonalities in the approach to quality management and specic related aspects were identied and summarized in a survey report (www.EUBIS-europe.eu) [7]. It identied some of the perceived high-risk areas in blood collection, preparation, laboratory testing, storage and distribution with 7 of 15 (47%) participating blood establishments of the view that their present SOP system required change in the light of the European blood legislation, These were mainly participants from the member states that joined the EU in 2004 and from the applicant countries (Bulgaria and Romania joined the EU in 2007). Four of 15 (27%) participants (2 from Applicant Countries and 2 from the 15 pre2004 EU member states) indicated that their blood establishments were not inspected by government authorities. The responses also led to the identication of critical areas in transfusion medicine that needed to be addressed by the projects working groups. The structure of the working groups and their area of coverage are presented in Table 1. The participating blood establishments agreed on the common quality elements for SOPs (Fig. 1). Depending on the national requirements, blood establishments have also to follow specic regulations dened by the good manufacturing practice (GMP) and/or the standards of the International Organisation for Standardisation (ISO) for setting-up a quality manual or site-master le. In these cases, it will be advisable to cross-reference the directive requirements to those standards in order to harmonize the quality management system.

Overview of quality principles of Directives 2002/98/EC and 2005/62/EC

Directive 2002/98/EC [3] denes criteria and information to be provided by each blood establishment to the competent authority for the purpose of designation, authorization, accreditation or licensing in accordance with Article 5(2). In part B of Directive 2002/98/EC, the description of the quality system has to include: (1) an organization chart, including responsibilities of responsible persons and reporting relationships; (2) a site master le or quality manual describing the quality system in accordance with Article 11(1); (3) number and qualications of personnel; (4) hygienic provisions; (5) premises and equipment; (6) list of standard operating procedures (SOP) for - donor recruitment - retention and assessment of donors - processing and testing - distribution and recall of blood and blood components - reporting and recording of serious adverse reactions and events.

Methodology
A survey questionnaire was designed and sent out to all participants in order to evaluate the current standards used by the participating blood establishments in quality management systems. This survey was divided into four different sections specically addressing questions related to (1) basic validation, (2) principal management requirements, (3) areas of work, where SOPs are in place, i.e. donor recruitment, testing, management, logistics, etc., and (4) the way that risks are

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Table 1 Project working groups Working group 1 (WG 1): Donor recruitment and production WG-members: The Netherlands (leader), Cyprus, Iceland, Italy Topic Areas of interest and risk identied

Identication of donors and labelling - Blood Collection - Donor Identication - Donor acceptability/selection/interview - Disinfection and Sterility of blood components - Labelling and Identication

Working group 2 (WG 2): Testing (immunohematology, molecular diagnostics) WG-members: United Kingdom (leader), Belgium, Bulgaria, Romania Topic Areas of interest and risk identied

Blood group determination and compatibility testing in emergency - Testing of blood groups and labelling (Rhesus variants/ABO) - Testing in emergencies - Donor registries (could be linked to section IV)

Working group 3 (WG 3): Special blood component production WG-members: Germany (leader), Czech Republic, Hungary, Malta, Poland Topic Areas of interest and risk identied

Processing of platelet apheresis concentrates - Apheresis concentrates (platelets) - Pooled platelet concentrates - Granulocyte concentrates - Pediatric units

Working group 4 (WG 4): Logistics, storage, distribution and management WG-members: France (leader), Estonia, Ireland, Scotland Topic Additional guidelines Areas of interest and risk identied

Validation of temperature control areas for storage and transportation of blood components Change control of documents - Transportation and temperature control - Validation of equipment - Central blood stock management and distribution - Blood component release and/or issuing - Storage and transport related to production

Directive 2005/62/EC [6] sets out standards and specications related to a quality system for blood establishments, based on Directive 2002/98/EC, that will help to ensure the safety of blood throughout the European Union. A quality system for blood establishments should embrace the principles of quality management, quality assurance and continuous quality improvement, and should include personnel, premises and equipment, documentation, collection, testing and processing, storage and distribution, contract management, nonconformance and self-inspection, quality control, blood component recall, and external and internal auditing. (refer to Directive 2005/62/EC, recital (3)). A quality system for blood establishments is a key element in the implementation of good practice. Quality management system should ensure a systematic approach towards quality and the implementation and maintenance of a quality system. These QMS should involve all persons and processes of the blood establishment (Annex 11, Directive 2005/62/EC).

Quality management system should also lead to a system to evaluate processes of blood establishments to lead to continuous improvement of quality. According to Directive 2005/ 62/EC quality systems for blood establishments should be based in good practice (GP). In order to ensure the highest quality and safety for blood and blood components, guidance on good practice should be developed to support the quality system requirements for blood establishments taking fully into account the detailed guidelines referred to in Article 47 of Directive 2001/83/EC so as to ensure that the standards required for medicinal products are maintained. (refer to Directive 2005/62/EC, recital (5)). There are no absolute criteria for framing the quality management system. In general, it comprises a number of tools dened by the individual institution in order to allow the exibility to adjust to various regulations and guidelines. In order to fulll these requirements, a blood establishment should establish a quality management system to be organized in

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Fig. 2 Document structure of the EU-Q-SOPmanual with SOP levels covered by the project manual. The gure represents the hierarchy of documents used by a quality management systems following good quality standards as dened by the Directive 2002/98/EC and its technical annexes. The quality manual or site master le should be established according to Annex I Part B, Art 11(1), Directive 2002/98/EC.

different levels of document responsibility. In general, the top level are the legislative instruments (e.g. legislation and laws), regulations and guidelines an individual blood establishment has to follow (Fig. 2). These regulations should be incorporated in the quality management system and reected throughout the whole quality documentation system. A description of the quality system has to be given in the document level directly below. In doing this, they will specically address the following as appropriate according to the annex of Directive 2005/62/EC: - General Principles (part 1) - Personnel and Organization (part 2) - Premises (part 3) - Equipment and Materials (part 4) - Documentation (part 5) - Blood collection, testing and Storage (Section 6) including 6165 (61 Donor Eligibility, 62 Collection, 63 Laboratory testing, 64 Processing and validation, 65 Labelling) - Storage (Section 7) - Contract Management (Part 8) - Non-Conformance (part 9) including 9194 (91 Deviations, 92 Complaints, 93 Recall, 94 Corrective and preventive actions) - Self-inspection, audits and improvements (part 10) The quality manual or site master le should be established according to Annex I Part B, Article 11(1), Directive 2002/98/EC. The site-master le or quality manual is the formal documentation of arrangements in place in the blood establishment

describing the activities hat need the requirements of the Annex of 2005/62/EC (see previous discussion parts 110). The developed SOPs must adhere to the quality principles set out in the quality manual or site-master le in keeping good documentation practice. In order to be in line with those principles, it is essential to have procedures dening: - change control; and - training personnel on SOPs. The requirements for these procedures are set out in Directive 2005/62/EC (Part 5 Documentation) (1) Documents setting out specications, procedures and records covering each activity performed by the blood establishment shall be in place and kept up to date. (2) Records shall be legible and may be handwritten, transferred to another medium such as microlm or documented in a computerized system. (3) All signicant changes to documents shall be acted upon promptly and shall be reviewed, dated and signed by a person authorized to perform this task. An SOP provides a series of instructions to carry out an activity. In order to demonstrate compliance with SOPs, records of these activities must be generated. Properly maintained records provide the evidence of adherence to procedures. Generally, records fall into the following categories: - electronic records; - manually generated records; - hybrid record (combination of electronic and manual records).

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Fig. 3 Schematic presentation of the minimum list required by an SOP.

The writing of SOPs is the responsibility of user departments. This should be carried out in co-operation with the quality function. A major aim in writing SOPs is to ensure that they are comprehensive but clear, simple and user-friendly. Based on the requirements described in previous discussions and on the individual quality management systems used by participants from 16 European member, acceding and EFTA states, the EU-Q-Blood-SOP project has developed a methodology for creating an SOP comprising the basic quality elements. This manual contains standards and practical examples aimed at assisting blood establishments in preparing for government inspections as required by Directive 2002/98/EC. It could also be used to adapt existing procedures to comply with current EU requirements. This SOP methodology comprises precise quality requirements, requisites and quality terms linked to the EU Directives and is based on GLP/GMP-standards that have to be specied (lled-out) in order to complete the documents (Fig. 3). These quality requirements are presented in a modular fashion in order to tailor the SOPs to meet local circumstances. The ultimate aim is to provide a logical framework that can be used by all institutions in a variety of different logistical and functional situations.

Combination of EU directive and accreditation and certication

The European directives have dened several key quality elements to achieved GMP in the eld of blood transfusion. These quality elements are very similar to quality policies set up by GMP or ISO standards. In recent years, several blood establishments throughout Europe have been certied using GMP and/or ISO standards. In line with this, ISO certication and accreditation have gained increasingly wider acceptance among blood establishments. Reasons for this are heterogeneous depending on the size of the blood establishment. Very often, large and complex blood establishments comprising several productions sites containing centralized facilities including equivalent logistics have moved to use ISO-based quality policies in order to optimize their quality management system. Additional reason can be the organizational position of blood establishments integrated in a hospital service. In those cases, ISO certication of the hospital could result in a co-certication of the blood establishment. Alternatively, accreditation and certication could be benecial, if the blood establishment

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supplies external hospitals that are certied and accredited. Accreditation and certication of blood component collectionproduction-issuing and/or patient diagnostics performed by the blood establishment using comparable standards and norms would facilitate the integration of the blood establishment in the overall quality strategy of those hospitals. Major benets from those quality management systems are: - the denition of an overall quality policy; - improved personnel responsibility, qualication and training; - error and risk assessment system; - continuous improvement; - improved resource management; - performance improvement. The evaluation of the costbenet relation resulting from certication and accreditation of blood establishments are complex and will depend on the individual institution itself and the amount of processes covered. With respect to the blood transfusion service Baden-Wrttemberg Hessen, certication and accreditation of the blood establishment has improved the quality in all of these areas. Short-term effects are very often limited in their positive costbenet relation; however, mid-term evaluation of improvements will results in positive costbenet relations, supporting the economic importance of good quality management systems. With the release of the new EU Directive 2005/62/EC, there are currently EU requirements available that describe in detail relevant processes to be covered by quality system following good practice used in blood establishments. A future challenge for transfusion medicine would be to optimize the synergetic effects expressed by the EU directive, GMP and ISO standards.

(Estonia); Alain Beauplet and Claudine Hossenlopp EFS (France); Saman Hosseini and Reinhard Henschler, RCBDS (Germany); Alan Slopecki NBS (UK), Klra Bartine-Tth and Eszter Miskovits, HNBT (Hungary); Sveinn Gudmundsson BTS (Iceland); William Murphy, IBTS (Ireland); Hamisa Jane Hassan ISS (Italy), Frances M. Delaney (Luxemburg), Alex Aquilina IBT (Malta); Elzbieta Lachert, IHBT (Poland); Carmen Tatu, FMP (Romania); Brian McClelland and Anne Forrest, SNBTS (Scotland).

References
1 Directive 2002/98/EC of the European Parliament and of the Council of 27 January 2003 setting standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components and amending Directive 2001/83/EC. Ofcial Journal of the European Union, L33, 8/02/ 2003, p. 30. (Also accessable at http://europe.eu.int). 2 Commission Directive 2004/33/EC of 22 March 2004 implementing Directive 2002/98/EC of the European Parliament and of the Council as regards certain technical requirements for blood and blood components. Ofcial Journal of the European Union, L91, 30/03/2004, p. 25. (Also accessable at http://europe.eu.int). 3 Commission Directive 2005/61/EC of 30 September 2005 implementing Directive 2002/98/EC of the European Parliament and of the Council as regards traceability requirements and notication of serious adverse reactions and events. Ofcial Journal of the European Union, L256, 1/10/2005, p. 32. (Also accessable at http://europe.eu.int). 4 Commission Directive 2005/62/EC of 30 September 2005 implementing Directive 2002/98/EC of the European Parliament and of the Council as regards Community standards and specications relating to a quality system for blood establishments. Ofcial Journal of the European Union, L256, 1/10/2005, p. 41. (Also accessable at http://europe.eu.int). 5 2004/192/EC: Commission Decision of 25 February 2004 adopting the work plan for 2004 for the implementation of the programme of Community action in the eld of public health (2003 to 2008), including the annual work programme for grants (Text with EEA relevance). Ofcial Journal of the European Union L60, 27.2.2004, p. 58. (Also accessable at http://europe.eu.int). 6 Community action in the eld of public health (20032008). (http://europe.eu.int/comm/health/ph_programme). Work plan 2005 following the Decision No 1786/2002/EC of the European Parliament and of the Council of 23 September 2002 adopting a programme of Community action in the eld of public health (20032008), Ofcial Journal of the European Union, L271, 9/10/2002. 7 Information on the EU-SOP Manual can be obtained from the Project homepage using eu-blood-sop.de or EUBIS-europe.eu. (Also accessable at http://europe.eu.int).

Acknowledgements
The EU-Q-Blood-SOP Project is co-funded by the European Commission Directorate C, Public Health Programme on quality and safety of blood, Project Grant Agreement n0 2004217. We would like to acknowledge the continuous and valuable contribution of all participating centres and participating experts in alphabetic member state order as follows: Eduardo Fernandez-Zincke, Tapani Piha, Caroline Trouet and Thomas Bregeon (EC, European Commission, Directorate C, Bruessels, Belgium); Inge Buyse and Philippe Vandekerckhove, HBRK (Belgium); Svetla Bakalova and Andrey Andreev, NBT (Bulgaria); Zoe Sideras MOH (Cyprus); Petr Turek, GTH (Czech Republic); Tatjana Plahhova and Riima Niidas, EBS

2007 The Authors. Journal compilation 2007 Blackwell Publishing Ltd. ISBT Science Series (2007) 2, 143149