Learning Material

The EuBIS manual aims to provides assistance to those countries/member states, that would like to implement quality standards and criteria for inspections commonly used. The EuBIS manual is based on regulatory requirements set out in Directives 2002/98/EC, 2004/33/EC , 2005/61/EC, 2005/62/EC and 2016/1214/EC. These include inter alia:
1) designation, authorisation, accreditation or licensing of blood establishments (BEs)
2) authorisation of the activities which can be undertaken and the applicable conditions for blood collection
3) provisions for ensuring the quality and safety of blood and blood components, and
4) requirements for imported blood and blood components.

The developed inspection standards and criteria assists in the independent assessment of quality system structures established by individual blood establishments in compliance with the EU legislation and/or international references used by the EuBIS project (e.g. PIC/S, CoE, GMP).

The Manual will assist blood establishments in preparing for inspections. The standards and checklists used for external inspections could be used for internal audits by blood establishments. With respect to the different standards and guidelines that are currently in place, the inspection guide summarizes the most critical aspects to be addressed in order to achieve good practice. For each of these critical points, the Training Guide provides references to commonly used standards for the inspection of BEs.

Defined principles for the structure of quality systems will assist in implementing or expanding the currently used quality management systems in blood establishments. Moreover, the manual will help to ensure the incorporation of standard operating procedures (SOPs) in a site master file or a quality management handbook reflecting GMP standards.

In order to prepare yourself for the course, please read the following chapters:

Chapter 5 - Self-Inspection of blood establishments
5.2.4.4 Site-master-File for blood establishments (also refer to Annex I)
5.3 Integration of quality risk management into self-inspection (also refer to EudraLex, Volume 4, Annex 20)
6.4 Planning for and assessment of an inspection
Chapter 7 - conduct of an inspection
Definitions for non-compliances (page 25, page 77 and Annex V, page 106)

The increasing diversity of processes covered by blood establishments, from blood components, pharmaceutical products, to tissue and cells, requires that quality systems need to be flexible in order to adapt to national and European quality requirements. Harmonisation of standards, therefore, would be useful. However, this has to take into account the different legal requirements of the European Union for pharmaceutical products, blood components and tissues and cells. In addition, despite transposition of EU Directives to the Member State level, national laws may require additional modifications for quality management systems. The EuBIS expert group has discussed the importance of those European and national standards in place and has developed a cross-reference guideline for quality management systems of blood establishments based on Directive 2005/62/EC. This cross-reference guideline includes the EU-GMP standards, the PIC/S GMP for blood establishments, the CoE Guide and the ISO 9000 series. By cross-referencing the relevant quality requirements to Directive 2005/62/EC, commonalities between these standards can be identified.

The EuBIS Audit/Inspection Training Guide aims to assist blood establishments (BE) in setting-up an inspection process. It is complementary to the EuBIS Manual on European inspection and self-inspection guide for blood establishments.

It comprises inspection criteria that cover the regulatory standards applicable within the European Union (EU) and based on its blood Directives. The criteria set out in the Guide, however, are not exhaustive and authorities and blood establishments may wish to supplement this material with additional requirements.

It is anticipated that this guide will prove useful for trainees involved in regulatory and self-inspections. The EuBIS Academy clearly recognises that additional inspection standards are used throughout Europe and/or Internationally/World-Wide. These standards reflect in part legal requirements defined by those States/Countries.

In particular, GMP standards are the basis for inspections carried out by competent authorities as well as blood establishments on the international level. The training guide, therefore, provides clear references to relevant GMP standards and refers to other commonly applied standards and guidelines used Internationally, such as the

- PIC/S guideline (Pharmaceutical Inspection Convention and Pharmaceutical Inspection Cooperation Scheme)

- CoE (EDQM) guide (Council of Europe) including the Good Practice Guideline (Directive 2016/1214)

The EuBIS Academy also acknowledges that ISO standards are used increasingly by blood establishments and hospitals for their diagnostic activities and to augment good manufacturing practice (GMP) and good clinical practice (GCP) guidelines.

The training material presented in Chapter 3 covers requirements applicable to blood establishments in the self-inspection process. The information is presented in the following tabular form, as follows:

Column 1 - Criterion number and primary reference to EU Directives
Column 2 - Sub-process / control point (the process step to which the audit criterion applies)
Column 3 - Cross reference source
Column 4 - Inspection criterion
Column 5 - Example evidence

The EuBIS Audit/Inspection Training Guide summarises the major processes to be audited or inspected as a part of a quality management system.

In order to prepare yourself for the course, we would recommend to study - in particular - the following chapters:

Chapter 3.3 Premises
3.3.1. Blood donor and collection area
3.3.2 Blood testing and processing area
Chapter 3.5 Blood collection, testing and processing
3.5.1 Donor eligibility
3.5.2 Collection of blood and blood components
3.5.3 Laboratory testing
3.5.4 Processing and validation
3.5.5 Labelling
3.5.6 Release of blood and blood components

The guide is complemented by documents (Annex I and Annex II) that are commonly used during inspections [e.g. modified site-master-file for blood establishments (SMF-BE), inspection record / trail] (Chapter 4.2.4)]. These documents facilitate the harmonisation of inspection processes and should assist in the documentation of observed non-compliances.

The site-master-file modified for blood establishments (SMF-BE) comprises information on the activity profile of the blood establishment, including the names of key personnel, facilities, equipment, documentation, contracts / agreements, complaints and product recalls and the quality system.

Information given by the SMF-BE will be used by the competent authorities in preparing and conducting the inspection.

It would be advisable for the blood establishment to regularly verify the information in the SMF-BE during self-inspection in order to be prepared for any regulatory / external inspection. Further details are presented in Annex I.

Please have a look at the following EuBIS template of a SMF-BE, that should be used - in part - during the training course in order to prepare an On-Site-Inspection.

For the training, it will be also very important to have these definitions present:
- Critical non-compliances
- Major non-compliances
- Other significant non-compliances
- Observations

Directive 2005/62/EC amended by Directive 2016/1214 sets out the technical requirements for blood establishments related to the implementation and maintenance of standards and specifications relating to a quality system. It covers general principles, personnel and organisation, premises, equipment and materials, documentation, blood collection, testing and processing, storage and distribution, contract management, non-compliances and self-inspection, audits and improvements.

As per the EU blood legislation quality shall be recognised as being the responsibility of all persons involved in the processes of the blood establishment with management ensuring a systematic approach towards quality and the implementation and maintenance of a quality system. The quality system encompasses quality management, quality assurance, continuous quality improvement, personnel, premises and equipment, documentation, collection, testing and processing, storage, distribution, quality control, blood component recall, and external and internal auditing, contract management, non-compliances and self-inspection. The quality system shall ensure that all critical processes are specified in appropriate instructions and are carried out in accordance with the standards and specifications set out in the blood legislation. Management shall review the system at regular intervals to verify its effectiveness and introduce corrective measures if deemed necessary.

All blood establishments and hospital blood banks shall be supported by a quality assurance function, whether internal or related, in fulfilling quality assurance. That function shall be involved in all quality-related matters and review and approve all appropriate quality related documents. All procedures, premises, and equipment that have an influence on the quality and safety of blood and blood components shall be validated prior to introduction and be re-validated at regular intervals determined as a result of these activities.

The primary piece of EU legislation related to blood is Directive 2002/98/EC. It lays down the general framework for ensuring quality and safety for the collection, testing, processing storage and distribution of blood and blood components. Complementary to it are three European Commission Directives which set out the technical requirements. In addition to Directive 2005/62/EC, Commission Directive 2004/33/EC specifies certain technical requirements for blood and blood components including definitions, information to be provided to and obtained from potential donors, donor eligibility criteria, including temporary and permanent deferral, quality and safety requirements and storage, transport and distribution conditions for blood and blood components. Commission Directive 2005/61/EC deals with requirements for the traceability of blood and blood components and the notification of serious adverse reactions and events.

In recent years, the European Commission has given guidance for the application and safety of preparations and components in the area of blood, tissue and cells by releasing several directives. Starting with Directive 2002/98/EC and followed by Directives 2004/33/EC, 2005/61/EC and 2005/62/EC for blood and blood components, the EC has defined requirements for the preparation of blood and blood components. Directive 2004/23/EC and more recently Directives 2006/17/EC and 2006/86/EC have given minimal requirements for the donation, procurement and testing process of tissue and cells and for traceability, severe adverse reactions (SAR) and events (SAE) as well as coding, processing, preservation, storage and distribution of tissue and cells.

The transplantation of human tissues and cells is a strongly expanding field of medicine offering excellent opportunities for the treatment of as yet incurable diseases. In order to minimise the infection risk involved in transplant operations, it is essential to ensure the quality and safety of the substances concerned. The Directives 2004/23/EC, Directives 2006/17/EC and 2006/86/EC therefore aim to establish high standards of quality and safety for tissues and cells of human origin for human therapeutic uses.

From a survey performed by EuBIS, it appears that the activity profile of several blood establishment include the donation, procurement and testing of tissue and cells. The EuBIS Academy gives therefore the references to the Basic 'Mother' Directive for Tissue and Cells and the 'Regulation' for ATMPs (Advanced Therapy Medicinal Products).

Despite the regulatory aspect of 'differences' between blood/blood components and tissue/cells, the quality management requirements are similar.

The Council of Europe (CoE, EDQM), which has been involved in issues related to blood transfusion since the early 1950s, has long advocated the principle of voluntary non-remunerated blood donation and promoted mutual assistance, optimal use, and protection of the donor and recipient. Complementary to the GMP guidelines, the Council of Europe has developed a Guide to the preparation, use and quality assurance of blood components [Recommendation No. R (95) 15]. The CoE (EDQM) Blood Guide is commonly used among blood establishments throughout the EU Member States and the countries joint under the CoE. Only in some EU Member States, e.g. Germany, do national recommendations surpass the CoE (EDQM) Blood Guide in its application for routine work.

The Blood Guide contains a compendium of measures designed to ensure the safety, efficacy and quality of blood components and is particularly intended for all those working in blood transfusion services.

Very importantly, the CoE Blood Guide provides guiding principles to be considered for the donation of blood and blood components and includes the Good Practice Guidelines (GPG) which provide standards for the implementation of quality systems in blood establishments and, where applicable, hospital blood banks. In accordance with European Commission Directive (EU) 2016/1214, the GPG should be taken into account by EU member states in the implementation of quality systems in blood establishments.

The Blood Guide is elaborated by a dedicated working group (the GTS) composed of internationally recognised experts. The GTS works under the aegis of the European Committee on Blood Transfusion (CD-P-TS) the steering committee responsible for blood transfusion activities at the Council of Europe.

The EuBIS Manual and Inspection/Audit Training Guide refers to the content of the CoE Blood Guide by giving references on the EuBIS criterion numbers in the EuBIS Inspection/Audit Training Guide (see also Essential - 2)

For those interested in receiving further information on the CoE guide or to receive (order) the CoE Blood Guide, please refer to https://www.edqm.eu/en/blood-guide

PIC/S is the acronym for the Pharmaceutical Inspection Convention / Co-operation Scheme. These are instruments between countries and pharmaceutical inspection authorities, which together provide active and constructive co-operation in the field of Good Manufacturing Practice (GMP).

PIC/S has as its mission to lead the international development, implementation and maintenance of harmonised (GMP) standards and quality systems of inspectorates in the field of medicinal products. It aims to do this by developing and promoting harmonised GMP standards and guidance documents; training competent authorities, in particular inspectors; assessing (and reassessing) inspectorates; and facilitating the co-operation and networking for competent authorities and international organisations. There are currently 40 Participating Authorities in PIC/S (Convention and Scheme taken together). Its expert circle on blood and tissue was founded by the Paul-Ehrlich-Institute (PEI) in 1994 recognizing the need for specialized knowledge on these special issues related to blood and transmissible diseases.

In response to the need for a modification of EU-GMP standards, the expert circle on blood and tissues developed a GMP Guide for blood establishments. This PIC/S GMP Guide intends to facilitate the introduction of GMP standards for blood and apheresis establishments and is used by PIC/S inspectors in assessing the quality management systems of those establishments. Although the Guide follows the structure of the EU GMP standard, it addresses specific processes to be covered in the collection, preparation and distribution of blood and apheresis components, such as blood donor areas, mobile donor sessions, irradiation of blood components or whole blood collection and component preparation.

The EuBIS guide refers in its Critical Sub-Proecesses by criterion cross references to the PIC/S guide for the inspection of blood establishments (see enclosed file 1)

In addition, the EuBIS Academy would recommend to study risk based inspection approaches using the document of PIC/S (see enclosed file 2). This document refers also to Chapt. 5.3 of the EuBIS manual.

The EU-GMP standard (EudraLex) gives detailed and very specific standards for the production of pharmaceutical components. In particular blood establishments that perform cryoprecipitation or the collection of source plasma for fractionation have established quality management systems that relate to these standards. In some Member States, e.g. Germany, where pharmaceutical legislation applies for all blood components, the EU-GMP standard is mandatory.

The EU-GMP standard give detailed specifications for quality management, personnel, premises and equipment, documentation, production, quality control, contract manufacturers and analysis, complaints and recall and self- inspections.

In addition, Annex 2 (biological products) and Annex 14 (blood components) of the EU-GMP standard are used as specifications for plasma fractionation. Both EU-GMP annexes contain requirements and specifications that can be adapted to the production of standard blood components and are used inter-alia by blood establishments.

In contrast, several standards defined by EU-GMP are derived from specific production, storage and distribution characteristics of pharmaceutical production processes, such as process monitoring of intermediate and bulk products, batch processing records or ongoing stability programme to monitor the product over its shelf life. These EU-GMP standard requirements are more suited to the manufacturing facilities and production processes for medicinal products by the pharmaceutical industry and are difficult to adapt to standard blood component collection, preparation and distribution as covered by Directive 2002/98/EC.

In preparing for the EuBIS course, we would like to refer to Chapter 5.3 of the EuBIS manual, were we give a comprehensive explanation on quality risk management.

Further readings would also refer to EudraLEX
https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-4_en

Member States shall take into account the Good Practice Guidelines (GPG) jointly developed by the Commission and the European Directorate for the Quality of Medicines and Healthcare (EDQM) of the Council of Europe and published by the Council of Europe. GPG is amended by COMMISSION DIRECTIVE (EU) 2016/1214 of 25 July 2016 amending Directive 2005/62/EC as regards quality system standards and specifications for blood establishments.

The GPG is included in the CoE (EDQM) Blood Guide (see Essentials 4 and 6).

This guideline by the EMA (European Medicine Agency)provides principles and examples of tools for quality risk management that can be applied to different aspects of pharmaceutical quality. These aspects include development, manufacturing, distribution, and the inspection and submission/review processes throughout the lifecycle of drug substances, drug (medicinal) products, biological and biotechnological products (including the use of raw materials, solvents, excipients, packaging and labelling materials in drug (medicinal) products, biological and biotechnological products).

An effective quality risk management approach can further ensure the quality of the drug (medicinal) product to the patient by providing a proactive means to identify and control potential quality issues during development, manufacturing, and distribution. This includes an appropriate application of root cause analysis that can identify and address the root cause(s) and other causal factors (e.g., human-related) of such issues.

A proactive approach to quality risk management is beneficial, as it facilitates robust product design and continual improvement, and it is of strategic importance in achieving an effective pharmaceutical quality system. (See ICH Q10 for guidance in relation to an effective pharmaceutical quality system.) Additionally, use of quality risk management can improve the decision-making if a quality problem arises.

The Good Practices for demonstrating safety and quality through recipient follow up Project (hereinafter referred to as "EuroGTP II") project, developed the tools and methodologies to aid tissue bankers and healthcare professionals in the evaluation of safety, quality and efficacy of tissue and cellular therapies and products - Good Practices for evaluating quality, safety and efficacy of novel tissue and cellular therapies and products1 - therefore providing effective care of their patients. The current guidance aims to provide similar aid to professionals of Blood Establishments (BE), Hospital Blood Banks (HBB), and other health professionals responsible for the clinical use or assessment of quality and safety of Blood Components (BC) (i.e. Competent Authorities (CA)).

The Euro GTP II Methodologies (Annex I. Methodologies Wall Chart) and Interactive Assessment Tool (IAT) have been developed to assist professionals involved in the provision of BC to:
- Determine if a BC or preparation process has any novelty (Step 1)
- Assess the risks associated with the BC or preparation process (Step 2)
- Determine the extent of any studies and/or follow up required to assure the safety and efficacy of BC (Step 3)

This guide has been developed under work package 6 of the VISTART Joint Action funded by the European Commission, Health and Consumer Protection Directorate General, Public Health and Risk Assessment Directorate, DG Sante Directorate General Sante and the Consumers, Health and Food Executive Agency (Grant Agreement No. 676969). The key objectives of the VISTART Joint Action are to promote and facilitate the harmonisation of the inspection, authorisation and vigilance systems for blood, tissues and cells (including reproductive cells).

Reference: https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e5b1d517f8&appId=PPGMS