QUALITY MANAGEMENT for Blood Establishments

1st European Training Course QUALITY MANAGEMENT for Blood Establishments

BLOOD-QUALITY EDQM, Strasbourg, PROCEEDINGS MANAGEMENT WORKING France GROUP (B-QM WG) Trainee Toolkit 14 - 17 April 2015

B-QM Programme

European Directorate Direction européenne for the Quality de la qualité of Medicines du médicament & HealthCare & soins de santé 1st EUROPEAN TRAINING COURSE: QUALITY MANAGEMENT For Blood Establishments 2015

European Directorate for the Quality of Medicines & HealthCare (EDQM)

Council of Europe, EDQM These proceedings are published by the European Directorate for the Quality of Medicines & HealthCare (EDQM) of the Council of Europe.

All rights conferred by virtue of the International Copyright Convention are specifically reserved to the Council of Europe and any reproduction or translation requires the written consent of the Publisher.

Director of the publication: Dr S. Keitel

Page layout and cover: EDQM Cover illustration: ©Shutterstock

European Directorate for the Quality of Medicines & HealthCare (EDQM) Council of Europe 7 allée Kastner, CS 30026 F-67081 Strasbourg France

Website: www.edqm.eu For accessing the publication: https://register.edqm.eu/freepub FAQs & EDQM HelpDesk: www.edqm.eu/hd

This training course was organised by the EDQM in the frame of the Blood Quality Management Programme, an activity carried out with funding by the European Union and by the Council of Europe. This document was produced with financial assistance by the European Union. The views expressed herein can in no way be taken to reflect the official opinion of the European Union. Contents

FOREWORD AND WELCOME ADDRESS 4 PROGRAMME 7 TRAINERS 14 LIST OF PARTICIPANTS 15 PURPOSE OF THE TRAINING COURSE 17 PRESENTATIONS 18 OPENING SESSION 18 MODULE A–REGULATORY FRAMEWORK AND QUALITY MANAGEMENT 33 EUROPEAN REGULATORY FRAMEWORK FOR THE QUALITY AND SAFETY OF BLOOD 34 COMPONENTS FOCUS ON QUALITY STANDARDS USED IN BLOOD ESTABLISHMENTS 41 QUALITY- WHAT IT IS 52 MODULE B–MANAGEMENT PROCESSES 60 ORGANIGRAM – ORGANISATIONAL CHART 61 MANAGEMENT OF QUALITY DOCUMENTATION 69 TRAINING IN QUALITY MANAGEMENT SYSTEMS 82 MODULE C–SUPPORT PROCESSES 94 RISK IN PERSPECTIVE 95 INTRODUCTION TO RISK MANAGEMENT TOOLS 103 QUALIFICATION: A RISK-BASED APPROACH 114 MODULE D–REALISATION PROCESSES 124 KEY PERFORMANCE INDICATORS IN BLOOD ESTABLISHMENTS 125 QUALITY CONTROL & STATISTICAL PROCESS CONTROL 131 MODULE E–CONTINOUS IMPROVEMENT 143 MANAGEMENT OF NON-CONFORMITIES 144 CHANGE CONTROL 152 HAEMOVIGILANCE 164 INTERNAL AUDIT 174 MANAGEMENT REVIEW 185 LIST OF DEFINITIONS 191 LIST OF ACRONYMS 194 LIST OF AUTHORS 195

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Foreword

ounded in 1949, the Council of Europe is the oldest and largest of all European institutions and now numbers 47 Member States (MSs) 1 . One of its founding principles is increasing Fcooperation between Member States to improve the quality of life of all Europeans. Within this context of intergovernmental co-operation in the field of health, the Council of Europe has consistently worked on ethical problems. The most important such ethical issue relates to the non-commercialisation of human substances, i.e. blood, organs and tissues.

With regard to blood transfusion, co-operation among MSs started in the 1950s. Through its activities in the blood transfusion area, the Council of Europe has been actively contributing to the implementation of high standards for the protection of public health and the promotion of human rights and human dignity. Blood and blood components are essential for healthcare in Europe as they are used to provide treatment to citizens. They are essential in major surgery. Furthermore, treatments of traumas, acute bleeding and also several chronic diseases such as thalassemia rely on the availability of blood. Since the 1950s, the Council of Europe has elaborated a number of agreements and recommendations2 covering ethical, social, scientific and training aspects of blood transfusion. Whereas agreements are binding for the States that ratify them, recommendations are policy statements to governments proposing a common course of action to be followed. Work in the field of Quality Assurance (QA) started in the 1980s. The major recommendations in this field include Recommendation No. R (95) 15 and its technical Appendix, which has now become the Guide to the preparation, use and quality assurance of blood components” referred hereafter as the “Guide”. The purpose of the Guide is to provide blood establishments with a set of standards and principles relating to the preparation, use and quality assurance of blood components. The Guide covers all blood components that will be prepared at a blood establishment but does not cover plasma products obtained by fractionation. In respect of plasma-derived products, technical matters are addressed by the European Pharmacopoeia whereas the European Union has a substantial body of legislation including plasma-derived products. On 27 January 2003 the European Union adopted Directive 2002/98/EC on setting standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components.

1 Albania, Andorra, Armenia, Austria, Azerbaijan, Belgium, Bosnia and Herzegovina, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Georgia, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Liechtenstein, Lithuania, Luxembourg, Malta, Republic of Moldova, Monaco, Montenegro, Netherlands, North Macedonia, Norway, Poland, Portugal, Romania, Russian Federation, San Marino, Serbia, Slovak Republic, Slovenia, Spain, Sweden, Switzerland, Turkey, Ukraine, United Kingdom.

2 http://www.edqm.eu/en/blood-transfusion-recommendations-resolutions-71.html

Page 4 As regards technical requirements to be set under Article 29 of the said Directive, the European Commission and the Council of Europe work closely together to ensure that these requirements are compatible with the Guide. Whereas blood establishments in EU Member States are required to comply with legislation derived from the European Commission Directives, the Guide is intended to facilitate ongoing improvements in the preparation, use and quality assurance of blood components through education and the provision of non-binding recommendations. The Guide therefore provides additional information and guidance on best practices consistent with current scientific knowledge and expert opinion. Implementation of these recommendations may vary among MSs and individual blood transfusion establishments, and alternative procedures, practices and standards may be in place. In 2007, the Secretariat with responsibility for activities related to blood transfusion was transferred to the European Directorate for the Quality of Medicines & Healthcare (EDQM) of the Council of Europe. In 2010, as a result of cooperation with the Commission of the European Union, and with a view to improving the safety of labile blood products and of patients undergoing blood transfusion, the EDQM implemented the Blood Proficiency Testing Scheme (B-PTS)3, an External Quality Assessment (EQA) programme dedicated to European blood establishments. The EDQM realised over time that, with the complexity of available standards in the field of blood transfusion, European blood establishments did encounter difficulties in implementing a comprehensive and integrated Quality Management System (QMS). For this reason, the EDQM decided to further develop its activities in the field of Quality Management. In 2012, the Blood Quality Management (B-QM) activity was set up. As an assistance and educational activity, it includes the provision of on-site training courses, visits and an audits scheme4. The decision was taken in 2013 to complement these activities with learning activities, and therefore to organise a Training Course on Quality Management for European blood establishments. This Quality Management programme has been elaborated with the input of experts working in blood establishments. Special thanks should be given to all these experts for their contributions, efforts and commitment, in particular to: Alina Dobrota, Director, Regional BTC, Romania Beate Rothe, Head of Department, Klinikum Wolfsburg, Germany Mariëlle Van Roosmalen, Compliance Officer, Sanquin, Netherlands Alex Aquilina, Director, NBTS, Malta Jan Ceulemans, Quality Manager, HBRC-Flanders, Belgium Oliver Kürsteiner, Head of Quality Management, SRK, Switzerland Martin Pisacka, Head of Immunohematology Department, UHKT, Czech Republic

The members are also grateful to the European Committee on Blood Transfusion (Partial Agreement) (CD-P-TS) members who support the B-QM Working Group (B-QM WG) and the EDQM in the implementation of these recent activities.

These proceedings reproduce the presentations with the kind permission of the trainers. Their preparation and publication was co-ordinated by Marie-Laure Hecquet, Scientific Officer responsible for the B-PTS and B-QM activities, with the assistance of Nevena Kojic and Béatrice Barth.

3 https://www.edqm.eu/en/blood-proficiency-testing-scheme-b-pts 4 https://www.edqm.eu/en/blood-quality-management-programme-b-qm

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Welcome Address

Dear Colleagues, Dear Friends,

The concept of Quality Management has evolved greatly over the last decade while European blood establishments have constantly had to implement new regulatory requirements. Transfusion is a medical procedure that carries an intrinsic component of risks and implementation of a Quality Management system (QMS) in blood establishments is the key to managing risks and ensuring the efficacy, quality and safety of blood components.

Implementation of a QMS is required by EU Directives and prescribed in the Council of Europe Guide to the Preparation, Use and Quality Assurance of Blood Components. However, while it is a means of ensuring that quality and risks are under control, it is often regarded as a burden and a complicated process. Hence the need for a training course on Quality Management.

The EDQM Blood Quality Management Working Group (B-QM WG) has worked to set up a training course on Quality Management that meets the needs of European Blood Establishments.

We do believe that common knowledge of implementing a QMS would promote mutual confidence across European countries.

The 1st European Training Course on Quality Management for Blood Establishments is organised by the European Directorate for the Quality of Medicines & HealthCare (EDQM).

We are pleased to welcome all of you in Strasbourg and do hope that you will have fruitful discussions and exchanges.

“Quality Management system (QMS) in blood establishments is the key to managing risks and ensuring the efficacy, quality and safety of blood components”

Marie-Laure Hecquet Responsible Scientific Officer, DBO

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Programme

14 APRIL 2015 – MORNING SESSION

9:00-9:45 Opening & Welcome Address M.-L. Hecquet, Scientific Officer, EDQM

Introduction of the trainers and the participants - Ice Breaker M. Pisacka

9:45-10:15 INTRODUCTION TO THE TRAINING COURSE

10:15-10:45 MODULE A - REGULATORY FRAMEWORK FOR QUALITY MANAGEMENT SYSTEMS IN EUROPEAN BLOOD ESTABLISHMENTS

10:15-10:30 Lecture 1 - European Regulatory Framework for Quality Management Systems M.-L. Hecquet

10:30-10:45 Lecture 2 - Focus on Quality Standards used in Blood Establishments M.-L. Hecquet

11:20-12:15 Exercise 1: Gap Analysis- Audit report M. v. Roosmalen

12:15-12:30 Plenary Session- Exercise 1 A. Aquilina

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14 APRIL 2015 – AFTERNOON SESSION

13:30-17:00 MODULE B - MANAGEMENT PROCESSES

13:30-13:50 Lecture 4 - Why is an organigram useful? A. Aquilina

13:50-14:10 Exercise 2: Elaboration of the organigram of vBC A. Aquilina

14:10-14:20 Plenary Session - Exercise 2 A. Dobrota

14:20-14:50 Exercise 3: Role and Responsibilities within a BE Interactive Exercise – Quiz B. Rothe

15:05-16:05 Exercise 4: Process Mapping M.-L. Hecquet

16:05-16:40 Plenary Session - Exercise 4 J. Ceulemans

16:40-17:00 Sum-up Day 1 M.-L. Hecquet

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15 APRIL 2015- MORNING SESSION

9:00-11:10 MODULE B - MANAGEMENT PROCESSES

9:00-9:10 Exercise 5: Are you Awake? Interactive Exercise - Quiz M. Pisacka

9:10-9:50 Exercise 6: “Spot the errors” B. Rothe

9:50-10:05 Plenary Session - Exercise 6 A. Aquilina

10:05-10:30 Lecture 5 - Management of Quality Documentation M.-L. Hecquet

10:45-11:10 Lecture 6 - Training in QMS M. v. Roosmalen

11:10-12:00 MODULE C - SUPPORT PROCESSES

11:10-11:30 Lecture 7 - Risk in Perspective A. Aquilina

11:30-12:00 Lecture 8 - Introduction to Risk Analysis Tools J. Ceulemans

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15 APRIL 2015- AFTERNOON SESSION

13:20-16:00 MODULE C - SUPPORT PROCESSES

13:00-14:00 Exercise 7: Do I have a risk? A. Aquilina/J. Ceulemans

14:00-14:30 Plenary Session - Exercise 7 B. Rothe

9:50-10:05 Plenary Session - Exercise 6 A. Aquilina/J. Ceulemans

14:45-15:10 Lecture 9 - Qualification and Validation A. Aquilina

14:45-15:30 Exercise 8: How to qualify/validate an equipment/method? J. Ceulemans

15:30-16:00 Plenary Session- Exercise 8 A. Aquilina

16:00-16:20 Exercise 9: What a wonderful day! Interactive Exercise - Quiz A. Dobrota

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16 APRIL 2015- MORNING AND AFTERNOON SESSIONS

11:30-13:00 MODULE D - REALISATION PROCESSES

11:30-12:30 Exercise 10: Process under Control? B. Rothe/M. Pisacka

12:30-12:50 Plenary Session - Exercise 10 M. Pisacka/B. Rothe 12:50-13:00 Lecture 10 - Introduction to Quality Indicators/KPIs J. Ceulemans

14:00-14:30 MODULE D - REALISATION PROCESSES

14:00-14:15 Lecture 11 - Quality Control and Statistical Process Control A. Aquilina/J. Ceulemans 14:15-14:35 Exercise 11: Quality Control and Statistical Process Control Interactive Exercise J. Ceulemans/A. Aquilina

14:35-14:45 Plenary Session- Exercise 11 A. Aquilina /J. Ceulemans

14:45-18:00 MODULE E - CONTINUOUS IMPROVEMENT

14:45-15:05 Lecture 12 - Management of Non-Conformities M.-L. Hecquet

15:20-15:50 Exercise 12: Root-Cause Analysis of a Non-Conformity M.-L. Hecquet

15:50- 16:05 Plenary Session- Exercise 12 M. v. Roosmalen/A. Dobrota

16:05 -16:20 Lecture 13 - Change Management M. v. Roosmalen

16:20-17:00 Exercise 13: Change Management M. v. Roosmalen/J. Ceulemans

17:00-17:20 Plenary Session- Exercise 13

17:20-17:40 Lecture 14 – Haemovigilance B. Rothe

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17:40-17:50 Sum-up Day 3 M.-L. Hecquet

18:00-18:15 Welcome Address S. Keitel, EDQM Director

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17 APRIL 2015 -MORNING SESSION

9:00-10:00 EXAM

10:15-12:00 MODULE E - CONTINUOUS IMPROVEMENT

10:15-10:35 Lecture 15 - Management of Internal Audits J. Ceulemans

10:35-10:55 Lecture 16 - Management Review A. Dobrota

10:55-11:30 GENERAL DISCUSSION - ADDITIONAL QUESTIONS

11:30-11:45 CONCLUDING REMARKS - ATTESTATION OF PARTICIPATION

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Trainers

AQUILINA Alexander National Blood Transfusion Service, Director Malta CEULEMANS Jan Flemish Red Cross, Quality Manager Belgium DOBROTA Alina Mirella Regional Blood Transfusion Centre, Director Romania European Directorate for the Quality of HECQUET Marie-Laure Medicines & HealthCare (EDQM), Council of France Europe, Scientific Officer Interregionale Blutspende SRK AG, Head of KUERSTEINER Oliver Switzerland Quality Management Institute of Haematology and Blood PISACKA Martin Transfusion, Head of Immunohematology Czech Republic Department Institute of Clinical Chemistry, Laboratory and ROTHE Beate Transfusion Medicine - Klinikum Wolfsburg, Germany Head of Department VAN Marielle Sanquin Blood Supply, Compliance Officer Netherlands ROOSMALEN

This training course was organised by the EDQM and in the frame of the Blood Quality Management Working Group (B-QM) WG programme. The B-QM WG is a technical committee nominated by the European Committee on Blood Transfusion (Partial Agreement) (CD-P-TS).

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List of Participants

BROISE Frédéric European Directorate for the Quality of France Medicines & HealthCare (EDQM) CADERAS Doina Interregional Blood Transfusion Src Ltd Switzerland BOSCHETTI ELDEMIR Sibel Turkish Red Crescent General Directorate of Turkey Blood Services ERAKOVIC Nela Institute for Blood Transfusion of Montenegro Montenegro ESPADA MARTIN Raquel JACIE Spain GHIAZZA Paola AOU Città della Salute e della Scienza di Torino Italy GLOCK Barbara Austrian Red Cross, Blood Donation Center for Austria Vienna, Lower Austria and Burgenland HERMUNDSTAD Brita Akershus University Hospital Norway IVANOVA Elena Regional Blood Establishment/Rcth Bulgaria JOVANOVIC Radmila Blood Transfusion Institute of Vojvodina Serbia KAVANAGH Margaret Irish Blood Transfusion Service Ireland KOK Lotte Region Zealand, Tissue and Transfusion Denmark Services KORKOLAINEN Mirja Finnish Red Cross Blood Service Finland KRYZAUSKAITE Lina Vilnius University Hospital Santariskiu Klinikos Lithuania Blood Centre LABANCA Luciana Blood Component Production Centre A.O.U. Italy Città della Salute e della Scienza LJUBICIC Julijana Croatian Institute for Transfusion Medicine Croatia LOPEZ Dulce Spanish Medicines Agency Spain LOPEZ FRAGA Marta European Directorate for the Quality of France Medicines & HealthCare (EDQM) LUND Merete Eis Odense University Hospital Denmark MALVAUX Nicolas Red Cross Luxembourg Luxembourg MARTINIS Georges Alexandroupolis University General Hospital, Greece Transfusion Centre NILSSON Maria Department of Laboratory Medicine Sweden PEREIRA Paulo Portuguese Institute of Blood and Portugal Transplantation PHILIPPUS Frans Military Blood Bank Netherlands PISACKA Martin Institute of Haematology and Blood Czech Republic Transfusion RASOVIC Gordana Institute for Blood Transfusion of Montenegro Montenegro RICHARD Arnaud European Directorate for the Quality of France Medicines & HealthCare (EDQM) RILEY Marie National Blood Transfusion Service Malta RISTIMAE Raili North Estonian Medical Centre Blood Centre Estonia ROCHA Cristina Directorate General of Health Portugal SNYKERS Philippe Belgian Red Cross Belgium SREDZINSKI Dariusz Regional Blood Center of Bialystok Poland STONIENE Laimute National Blood Centre Lithuania URAN Apolonija Blood Transfusion Center of Slovenia Slovenia

Page 15 VARDY Stephen National Health Service Blood and Transplant United Kingdom (NHSBT) - Leeds VELKOVA Emilija Institute of Transfusion Medicine North Macedonia VOLAKA Natalja National Blood Service of Latvia Latvia

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Purpose of the Training Course

Implementation of a Quality Management System (QMS) is required by the EU legislation prescribed in the Council of Europe Guide to the Preparation, Use and Quality Assurance of blood components and the newly developed Good Practices Guidelines (GPG).

However, the concept of Quality Management has evolved greatly over the last decade while European blood establishments have constantly had to implement new regulatory requirements.

In 2012, the EDQM performed a survey which showed that European blood establishments encountered difficulties in implementing a QMS and understanding its concept. In addition, the use of standards varies between countries and even within countries.

While a QMS is a means of ensuring that quality and risks are under control, it is often regarded as a burden, and a complicated process.

This prompted the EDQM to initiate an appropriate Training Course with the aim of supporting European blood establishments in setting up, developing and further improving their QMS.

The EDQM wishes to harmonise QMS practices and provide a common and uniform knowledge and approach for developing a QMS in a sustainable way. We do believe that this should ultimately promote mutual confidence across European countries and contribute to ensuring the quality and safety of blood components.

In this course, participants acquired advanced knowledge on quality management and how to implement an integrated QMS in a blood establishment.

The topics of process mapping, management of a quality documentation system, the concepts of validation and qualification and risk management, CAPA management and continuous improvement were tackled by experts in the field.

The course comprised a series of lectures and practical exercises, including active learning and discussions.

A Certificate of attendance was issued at the end of the course. Acquired knowledge was evaluated at the end of the course with a written exam. Candidates performing well in the exam received an exam certificate.

The course was also an excellent opportunity to meet experts in the field, exchange best practices and initiate collaboration between all the participants.

The Training Course was intended for quality managers or those with responsibility for quality in a European Blood establishment.

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Presentations

OPENING SESSION

14 April 2015 - Opening & Welcome Address, M. Wierer & M.-L. Hecquet - Ice Breaker, M. Pisacka - EDQM Mission & Activities in the Field of Blood Transfusion, M.-L. Hecquet

- Setting-up the Scene

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1st European Training Course

QUALITY MANAGEMENT FOR BLOOD ESTABLISHMENTS

14 - 17 April 2015 EDQM, Strasbourg, France

WELCOME ADDRESS

Dr M. Wierer, Deputy Head of DBO

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ICE BREAKER

Introduction of the trainers and the participants

M. Pisacka

EDQM MISSION & ACTIVITIES IN THE FIELD OF BLOOD TRANSFUSION

M.L Hecquet

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THE COUNCIL OF EUROPE (CoE)

Founded in 1949 Intergouvernmental organisation Headquarters in Strasbourg 47 Member States

Primary Objectives: create a common democratic and legal area and ensure fundamental values: human rights, democracy and the rule of law Driving Bodies: the Committee of Ministers of Foreign Affairs and the Parliamentary Assembly

DO NOT GET CONFUSED

CoE - Different roles but shared values- EU Council of Europe European Union D 47 Member States 27 Member States 800 Million of Europeans 500 Million of Citizens RUL E MOFOC LAW R A C Y HUM N RIGHTS

 Refers to theses values in  Agree on minimum legal a deeper political and standards with the primary economic integration concern of developing and processes spreading the awareness on these values

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THE EUROPEAN DIRECTORATE FOR THE QUALITY OF MEDICINES & HEALTHCARE (EDQM)

A Directorate of the Council of Europe Creation in 1964: activities based on the Convention on the Elaboration of a European Pharmacopoeia 37 Member States  Partial agreement

MISSION: Contribute to the basic human right of access to good quality medicines and healthcare and to promote and protect human and animal health

How do we work? Experts, nominated by the Member States, provide the technical and scientific expertise to elaborate standards and provide input in various programmes.

EDQM ACTIVITIES Quality Anticounterfeiting medicines PharmaceuticalsControls High Quality Sharing Standards Expertise Cosmetics Collaboration

Blood Organ, Tissue & Transfusion Cells, Transplantation

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EDQM BLOOD TRANSFUSION ACTIVITIES

OUTCOMES: Recommendations, Resolutions, Annual reports, Guides, Quality Managament Programme GTS …….. B-QM B-PTS AG B-PTS Working Working Groups – Groups expertise Technical Technical CD-P-TS European Committee on Blood Transfusion(Steering Committee)

Non-commercialisation of substances of human origin Protection for both Self-sufficiency the donors & the Voluntary and non- recipients remunerated donation

GUIDE TO THE PREPARATION, USE AND QUALITY ASSURANCE OF BLOOD COMPONENTS Quality and Safety Standards to be used by the Blood Transfusion Establishments

Legal status: Annex to Recommendation (95)15 of the Committee of Ministers of the Council of Europe i.e. non binding legal instrument as such but possibility to use it as a reference in national binding legal instruments Sections: Standards: minimum requirements Principles: additional advance information Currently:17th Edition

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GOOD PRACTICE GUIDELINES

Identifies the quality system elements that must be met by blood establishments and hospital blood to comply with EU Directive 2005/62/EC (Article 2):

- quality system standards and specifications of Directive 2005/62/EC - quality system Standards and Principles derived from the Guide to the Preparation, Use and Quality Assurance of Blood Components (17th edition) - quality system elements derived from the detailed principles of GMP

ACTIVITIES REPORTS: Examples

Trend & observations on the collection, testing and use of blood and blood components in Europe (2001-2008)

Report of the survey on Blood supply management in member and observer states (2012)

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BLOOD-PROFICIENCY TESTING SCHEME

Method for measuring the performance of laboratories based on interlaboratory comparisons. AIM: B-PTS provides Blood Establishments (BEs) with an objective mean of assessing that the testing results (Viral markers e.g HIV, HBV, HCV; ABO Rhesus) for blood donations are reliable.

 Participation in PTS required by Blood EU Directive 2002/98/EC &prescribedbytheCouncil of Europe Guide to the Preparation, Use and Quality Assurance of Blood Components.  Proposed B-PTS: tests required in the Directive

(1) Dedicated to European BEs (2) Programme unique in Europe

BLOOD-QUALITY MANAGEMENT PROGRAMME

AIM: Assistance/Educational Programme to help BEs in establishing, developing a comprehensive and integrated Quality Management System (QMS) & improving it.

NEED - Existing norms/guidelines in European BEs varies between countries and even between BEs within a same country; - BEs seeking for help to develop and build an integrated QMS.

 Implementation of a QMS required by Blood EU Directive 2002/98/EC &prescribedbytheCouncil of Europe Guide to the Preparation, Use and Quality Assurance of Blood Components.

(1) Dedicated to European BEs (2) Programme unique in Europe

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B-QM PROGRAMME (2)

Learning QMS Tools On site Monitoring QMS Tools

QMS Training Manual Course B-TV B-MJV B-MJA (Ongoing)

Blood Training Visit (B-TV): On-site visit  educate staff on technical & QMS topics;

Blood Mutual Joint Visit (B-MJV): Observe the QMS under development and give recommendations/advice for improvement and/or implementation of the QMS;

Blood Mutual Joint Audit (B-MJA): check compliance of the QMS with CoE Guide/relevant standards implemented final  compliance assessment

B-QM PROGRAMME: VALUES

 “On-site” schemes  take into account specificities of the blood transfusion field; tailor-made auditing/training schemes  take into account all applicable Norms/Guidelines;

 Auditors: experts from European BEs  bring & share experience/knowledge;

 Less expensive than general accreditation provided by private bodies;

 Impetus to implement EU Blood & Cross Border Directives;

 Harmonisation of QM Practices in Europe  ultimate goal of agreeing on a common approach in the implementation of QMS;

 Improve Mutual Confidence between European BEs;

 Increase Exchange of Blood Components between countries.

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INTRODUCTION TO THE TRAINING COURSE

M.L. Hecquet

TRAINING COURSE PROGRAMME

- BASED ON THE PROCESS APPROACH;

- LEARN HOW TO SET UP A QMS REFLECTING ON PROCESSES AND QUALITY ELEMENTS;

- 5 MODULES – STRUCTURAL APPROACH:

- MODULE A (RED): REGULATORY FRAMEWORK & QUALITY - MODULE B (BEIGE): MANAGEMENT PROCESSES - MODULE C (GREEN) SUPPORT PROCESSES - MODULE D (BLUE): REALISATION PROCESS - MODULE E (YELLOW): CONTINUOUS IMPROVEMENT

IN EACH MODULE: LECTURES & EXERCISES

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TRAINING COURSE CONTENT: LECTURES

- LECTURES:

MA- L1 Module A –Lecture 1

TRAINING COURSE CONTENT: EXERCISES

FLOW OF LEARNING: - CASE STUDY - QUIZ

- Individual Exercises - Group Exercises - Interactive Exercises

Time

A 31

Module A – page 31

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TRAINING COURSE CONTENT: TOOLKIT (1)

- BINDER:

- GENERAL INFORMATION - EXERCISES ORDERED ACCORDING TO THE LETTER & COLOUR OF THE MODULES

DURING THE COURSE:

- HANDOUTS OF LECTURES

- MODEL ANSWERS TO EXERCISES (BLUE PAPER) - Reflect trainer’s view - Example of answers

TRAINING COURSE CONTENT: TOOLKIT (2)

- BINDER:

- ANNEXES: - ANSWERS TO PRE-ASSESSMENT QUESTIONNAIRE - ABBREVIATIONS - DEFINITIONS - SOCIAL INFORMATION

- CoE Guide 17th Ed. - Compilation of Standards (Directives, GPG, PIC/S)

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PRACTICAL ISSUES

- Coffee Breaks (2 per day); - Lunches (EDQM cafeteria – Buffet);

- Social Event: No-Host Dinner on Wednesday 15 April - (Further information to be provided on day 2); - Visit at the French Blood Establishment on Thursday 16 April (morning); - (Further information to be provided on day 2);

- Administrative issues: Nevena & Beatrice

FINAL EXAM: FRIDAY 17 APRIL at 9:00

- BE ON TIME: 8h50 in Room 100

- DURATION: 1h15 min

- 15 questions: - Open questions; - Multiple Choice Questions; - Based on Exercices & Lectures (except Lectures provided on day 4)

- LISTEN & PARTICIPATE!

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STARTING POINT OF THE TRAINING COURSE

- vBC: VIRTUAL BLOOD CENTER

- vBC Factsheet: information on the BE - Audit report (EDQM audit)

LEARNING STYLE: KOLB THEORY

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AND ESSENTIAL KEY FACTORS

- Humour (with a minimum of seriousness);

- Experience sharing;

- Collegial Atmosphere;

- Be open , don’t be shy, do not hesitate to ask questions;

- Be happy :-) and Enjoy!

QUESTIONS

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MODULE A- GENERAL REGULATORY FRAMEWORK

14 April 2015 - Lecture 1, European Regulatory Framework for the Quality and Safety of Blood Components, M.-L. Hecquet - Lecture 2, Focus on Q-Standards Used in Blood Establishments, M.-L. Hecquet - Lecture 3, Quality- What It Is? M.-L. Hecquet

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EUROPEAN REGULATORY FRAMEWORK FOR THE QUALITY AND SAFETY OF

BLOOD COMPONENTS Module A:Framework - Lecture 1 Regulatory

Trainer: M-L Hecquet Lecture 1 –Day 1

MA-L1

TEACHING AIM

 Understand European regulatory framework for blood establishments;  EU Directives, CoE guide, GMP, PIC/S, ISO Standards;  QMS level among CoE Member States.

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BLOOD COMPONENTS MA-L1 ALLOGENIC TRANSPLANT INTRINSIC IRREMOVABLE COMPONENTS OF RISKS, e.g: - Biological risk (blood type differences/immunological interaction); - Transmission of diseases; - Adverse events (medical intervention/recipients’equilibrium) - Errors during testing, processing, storage; - Administrative errors: identification, mislabelling……..

BLOOD COMPONENT DEFINITION: « Therapeutic constituent of blood (red cells, white cells, platelets, plasma) that can be prepared by various methods » (EU Directive 2002/98/EC)

WHY A REGULATORY FRAMEWORK ? MA-L1 ALL CONFIDENCE , EQUIVALENT & RECIPIENTS LEVEL OF SAFETY & QUALITY & CITIZENS

HEALTH RECIPIENTS PROTECTION & & CITIZENS IMPROVEMENT

PROCESSED QUALITY & SAFETY BLOOD

INTRINSIC RISKS BLOOD

AVAILABILITY OF BLOOD DONORS/ CITIZENS

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EU TREATY PROVISIONS MA-L1

Article 168- Treaty of the Functioning of the European Union (TFUE) « A High level of human health protection shall be ensured in the definition and implementation of all union policies and activities» « measures setting high standards of quality and safety »

EU Directives

28 Countries

EU BLOOD DIRECTIVES MA-L1

Mother Directive 2002/98/EC of the EP & of the Council of 27/01/2003 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 IMPLEMENTATING MEASURES

Tech. Directive Techn. Directive Techn. Directive 2004/33/EC of 22/03/2004 2005/61/EC of 30/09/2005 2005/62/EC of 30/09/2005 implementing Dir. implementing Dir. implementing Dir. 2002/98/EC as 2002/98/EC as regards 2002/98/EC as regards regards Community standards certain technical traceability requirements & and specifications relating to a requirements for blood notification of serious quality system for blood and blood components. adverse reactions and establishments. events.  http://europa.eu/legislation_summaries/public_health/threats_to_health/c1156 5_en.htm

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REGULATORY FRAMEWORK FOR BLOOD MA-L1

BLOOD ESTABLISHMENT FRACTIONATOR BLOOD

Blood Legislation Pharmaceutical Legislation 2001/83/EC

EU 2002/98/EC & Technical Directives 2003/94/EC - GMP

CoE Guide & Good Practice Guidelines CoE

GMP ISO Standards

ISO Standards National

SURVEY AMONG CoE MS: QMS LEVEL MA-L1

SURVEY – 2012: 186 ANSWERS/BEs – 33 COUNTRIES

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SURVEY AMONG CoE MS: USED MA-L1 STANDARDS

SURVEY AMONG CoE MS: MANDATORY MA-L1 STANDARDS

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SURVEY AMONG CoE MS: STANDARDS MA-L1 USED- PLASMA FOR FRACTIONATION

SUMMARY/CONCLUSION MA-L1

 Blood legislation is complex;  Level of implementation varies between countries, although some legislation is mandatory;  Use/implementation of standards in Europe varies from one country to another;  Use/Implementation of standards in Europe varies within the same countries;  Difficulties to implement legislation and standards;  Need for assistance programme  EDQM B-QM Programme;  Need for a training course on how to elaborate a QMS in this context.

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USEFUL LINKS/READINGS MA-L1

 http://europa.eu/legislation_summaries/public_health/threats_to_heal th/c11565_en.htm http://ec.europa.eu/health/documents/eudralex/vol-4/index_en.htm https://www.edqm.eu/en/blood-transfusion-guides-1608.html

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FOCUS ON Q- STANDARDS USED

IN BLOOD Module A:Framework - Lecture 2 Regulatory ESTABLISHMENTS

Trainer: M-L Hecquet Lecture 2 – Day 1

ELEMENTS OF A QMS MA-L2

- Quality system: management, quality policy, objectives - Personnel and organisation; - Premises, material, Equipment; - Documentation, record keeping; - Collection; - Testing and Processing; - Storage and Distribution; - Quality Monitoring & Control; - Quality indicators/KPI; - Contract Management; - Change Control; - Risk management; - Non-Conformities and CAPA management; - Haemovigilance; - Internal and external auditing; - Process and management review.

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COMMONALITIES BETWEEN MA-L2 STANDARDS (1)

ELEMENTS EU DIR. CoE G. GMP PIC/S ISO 9001 ISO 15189 QM: management, leadership, quality Absent policy, objectives Personnel and organisation Implicit, or Premises, material, Equipment slight Documentation, Record keeping reference

Collection Explicit, Description Testing or more general Processing Explicit, Storage and Distribution substantial description Quality Monitoring & Control Quality indicators/KPI B-QM WG©2015 EDQM, Council of Europe. All rights reserved. Training Course - April 2015 3

COMMONALITIES BETWEEN MA-L2 STANDARDS (2)

ELEMENTS

Absent EU DIR. CoE G. GMP PIC/S ISO 9001 ISO 15189 Contract Management

Change Control Implicit, or slight Risk management * reference Non-Conformities and CAPA management Explicit, Description Haemovigilance or more general Internal and external auditing Explicit, substantial Process and management review description

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PRE-ASSESMENT QUESTIONNAIRE MA-L2 PART 2 (QMS IN BE)- RESULTS

30 Total Responses

Complete Responses: 30 Blood Establishments: 28

Q16: Which of the following quality standards does your Blood Establishment have to follow?

Answered: 28 Skipped: 2

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Q17: Which of the following quality standards does your Blood Establishment follow on a voluntary basis?

Answered: 26 Skipped: 4

Inconsitent with previous results

Q18: In your Blood Establishment, do you have

Answered: 28 Skipped: 2

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Q19: Do you have a procedure on qualification/validation of equipment/methods in place?

Answered: 28 Skipped: 2

Q20: Have you been already inspected by a Health Authority/National inspection body?

Answered: 28 Skipped: 2

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Q21: Are self-inspections/internal audits performed?

Answered: 28 Skipped: 2

Q22: Do you have a haemovigilance system or adverse reactions/adverse events system in place? If yes, please indicate whether the system is national- or local- based?

Answered: 28 Skipped: 2

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Q23: Do you have system to manage non-conformances/non-conformities (e.g. anomalies, deviations, out of specifications, complaints) in place?

Answered: 28 Skipped: 2

Q24: Do you have a system for corrective and preventive actions?

Answered: 28 Skipped: 2

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Q25: Do you have a recall procedure in place?

Answered: 28 Skipped: 2

Q26: Do you have a procedure for managing changes?

Answered: 28 Skipped:2

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Q27: Do you have outsourced activities ?

Answered: 27 Skipped: 4

Q28: Do you have a regular management review?

Answered: 28 Skipped: 2

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Q29: Do you have a procedure for training and qualifying employees?

Answered: 28 Skipped: 2

Q30: Do you have job description for key personnel?

Answered: 28 Skipped: 2

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SUMMARY/CONCLUSION

 EU directives do have to be implemented in EU countries;  Not all BEs are inspected yet by national authorities;  Not all QMS elements are in place;  Standards to be regarded as complementary;  Gap between standards and implementation which might only be filled in by appropriate tools such as training and audits

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QUALITY….. OH MY GOD….

LET’S GO BACK HOME ModuleLecture A: 3 Quality -

Trainer: M-L. Hecquet Lecture 3 - Day 1

MA-L3

TEACHING AIM

 Understand quality concepts;  Understand the process approach.

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QUALITY, THIS IS…… MA-L3

Who is willing to give a definition?

1) Quality of the product

N T NLY !

BUT ALSO …………. MA-L3

2) Quality of the processes which are carried out to produce a product or to provide clients/patients with a service

 Direct your organisation and processes towards quality;

 Ensure all processes are consistent, under control and are continuously improved;

e.g. - good management processes; - good recruitment, training processes; - good validation/qualification of equipment; - good reagents; - good premises; - good quality documentation etc…

BUT WHAT DOES “GOOD” MEAN?

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MA-L3 HOW TO ACHIEVE « GOOD » PROCESSES?

 PLAN and write “What to do”: describe your processes , sub- activities and tasks and responsible personnel;  In accordance with applicable standards, internal policies and PLAN other requirements (hospitals, recipients etc…);  Trained personnel  Procedures, so that they can implement “What to do” (procedure) in a consistent way; ACT DO  DO what is written;  Records outputs/critical data of your processes: temperature, raw CHECK data, interpreted data…..Traceability!!!  CHECK whether the data/results meet process and products specifications;  Use the outputs/results to improve process : update what you have written and ACT.

MA-L3 ITERATIVE 4 STEPS QM METHOD: PDCA

ACT PLAN Apply actions for Establish quality policy, objectives improvement. and processes (Process Review all steps (Plan, Do, mapping, procedures, forms) Check, Act) and update necessary to deliver results in processes to improve them accordance with the before next ACT PLAN specifications. implementation.

Continuous Improvement

CHECK DO CHECK Monitor, evaluate processes/ results/outputs against objectives/specifications and DO records Implement processes as planned and written

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LET’S TALK THE SAME LANGUAGE (1) MA-L3

QUALITY - “Degree to which a set of inherent characteristics fulfils requirements” (ISO 9001)

 Specifications for blood products are fulfilled;  Quality Control Testing.

QUALITY ASSURANCE - Implement procedures so that requirements for a product/service are fulfilled

 Procedures in place for the transfusion chain processes;  Quality assurance function.

LET’S TALK THE SAME LANGUAGE (2) MA-L3

QUALITY MANAGEMENT SYSTEM

- System level: Organisational structure, processes, procedures Quality Manager function;

- Management level: -To direct and control an organisation towards quality - Top-down Management - Quality policy and quality objectives

Independent from the Norms/guidelines implemented in the BE or from what your are doing in your organisation

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EVOLUTION OF QUALITY MA-L3

PRO-ACTIVE

Total Quality Management Quality REACTIVE Management System Product Quality Product Assurance Processes Processes Organisation Product Organisation Processes -Strategic Quality - Quality policy & planning - Procedures objectives - Quality cost and -Leadership productivity - Personnel (Lean, 6 Sigma) implication Product -Customersfocus & interested -Product parties requirements - Continuous - Quality control Improvement

BUILDING A QMS MA-L3

APPROACH  “STANDARDS/CHAPTERS” -Structured - Incompatibility if more than 2 APPROACH -Easyelaboration standards to follow Follow the structure of a standard (chapter, - Rigidity sections….) - No interaction between unit -Redundancy “FUNCTIONAL OR SERVICE “ -Structured - Rigidity APPROACH -Easyelaboration - No interaction between unit Grouped by entities/responsibilities -Redundancy (Laboratory, Quality Unit, Processing unit)

PROCESS APPROACH - Structured and Integrated - Requires grouping requirements Based on activities and commonalities - Takes into account interactions of different standards for a given between processes and process personnel - Requires good knowledge of all - Management, continous applicable standards improvement and support processes taken into account - Compatibility with other standards - No redundancy - Long term life

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QMS IN BLOOD ESTABLISHMENTS – PROCESS MA-L3 APPROACH  INTEGRATED QUALITY MANAGEMENT SYSTEM  STANDARDS: SYSTEM & TECHNICAL  TRANSVERSAL APPROACH

MANAGEMENT PROCESSES

Piloting: Management of Q-Documentation/ Improvement: Management of non- Management staff ….. conformance, Management of audits ISO 9001 REALISATION/CORE PROCESSES

SELECTION DISTRIBUTION/ COLLECTION TESTING PREPARATION RELEASE MEASURE/

IMPLEMENT DONORS ISSUING IMPROVEMENT

SUPPORT PROCESSES

VALIDATION/QUALIFICATION EQUIPMENT/ MAINTENANCE/ PURCHASING/

EU DIRECTIVES, CoE GUIDE, PIC/S

EU GMP 11 ISO 15189 * Not restrictive

PROCESS: WHAT IS IT? MA-L3

DEFINITION: Process is any set of interrelated or interacting activities which transforms inputs into - Requirements outputs (ISO 9000:2005) -Products - What is needed - Results achieved

INPUT PROCESS OUTPUT

FEEDBACK

RESOURCES: PERSONNEL, DOCUMENTATION, EQUIPMENT….

An output of an upstream process often becomes the input for a downstream process  INTERNAL CLIENTS

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CATEGORIES OF PROCESSES MA-L3

Management/piloting processes include planning, strategical, management, overseen activities directing processes towards quality;

Realisation/core processes include direct customers/patients related processes such as collection, processing, testing;

Support processes are assisting processes such as maintenance, validation of equipment.

SUMMARY/CONCLUSION

Adopting the process approach allows:  Managing and controlling processes;  Managing interactions between processes;  Understanding the importance of your work for your collaborators;  Integrating, aligning and linking processes effectively to achieve planned goals and objectives;  The organisation to focus on improving processes, effectiveness and efficiency; It also:  Facilitates the involvement and empowerment of people and the clarification of their responsibilities;  Promotes the smooth and transparent flow of operations within the organisation.

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USEFUL LINKS/READINGS MA-L3

 ISO 9000 Standard – QM Terminology ISO 9001 Standard – as a System/QM Standard

Page 59 8

MODULE B- MANAGEMENT PROCESSES

14 April 2015 - Lecture 4, Organigram – Organisational Chart, A. Aquilina

15 April 2015 - Lecture 5, Management of Quality Documentation, M.-L. Hecquet - Lecture 6, Training in QMS, M. v. Roosmalen

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ORGANIGRAM - ORGANISATIONAL

CHART Module B:Processes Management - Lecture 4

Trainer: Alex Aquilina Lecture 4 - Day 1

MB-L4 TEACHING AIM

 Understand the goal of an organigram;  Get knowledge on how to elaborate an organigram.

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REGULATIONS MB-L4

Directive 2002/98/EC – Annex I

Information to be provided to the CA for the purposes of designation, authorisation, accreditation or licensing in accordance with article 5(2):

Part B: Documentation such an organisation chart, including responsibilities of responsible persons and reporting relationship.

CoE Guide

There must be an organisation chart showing the hierachical structure and with clear delineation of lines of responsibilities

EU GMP – Chapter 2

2.2. The manufacturer must have an organisation chart.

ISO 9001

Top management shall ensure that responsibilities and authorities are defined and communicated within the organisation.

MB-L4 WHAT IS AN ORGANIGRAM?

Organisational structure is an important part of any organisation. It helps you: - to understand the communication and reporting flow (who reports to whom) within the organisation; - to understand the line of responsibilities.

Organigram is: A diagram (visual display) that shows the structure of an organisation and the relationships and relative ranks of its parts and positions/jobs. Relationship: - one official/person to another; - one department to another; - one function to another.

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MB-L4 DID YOU KNOW?

Egyptians  First people to use charts to illustrate the division of labour employed for large projects like the building of the Pyramids

WHY ? MB-L4

ORGANISATION CHART - Effective way to communicate organisational, employee and enterprise information; - Makes it easier for personnel to comprehend and digest large amounts of information as a visual picture (rather than as a table of names and numbers); - Provide the greatest value when used as a framework for managing change and communicating current organisational structure.

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USE OF OC MB-L4

- Organisational and supervisory communication; - Workforce planning; - Departmental or team planning; - Framework for managing change; Managing change becomes much easier once everyone is able to visualize the organization; - Communicate operational information across the organisation; - Decision making about resources for managers; - Job analysis: quick visualisation of the organisation with access to salary, gender and tenure information needed for decision-making purposes; - Organisational restructuring or redesign.

HOW SHOULD IT BE? MB-L4

Clear and Concise • Invaluable tool for management

Clear responsibilities, titles and lines of • Facilitate Team organisation authority

• Communication of valuable organisational Distributing and information to all employees sharing • Sharing organisation strategic vision and responsibilities, dependecies and relatiosnhip

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LIMITATIONS MB-L4

- If done/updated manually: OC  quickly become out-of-date (especially in large organisations with regular staff turn over); - Show "formal relationships“ only ; no pattern of human (social) relationships; No horizontal relationships; - No information about the managerial style adopted (e.g. "autocratic", "democratic" or other); - In some cases, an organigraph  more appropriate, particularly if wish to show non-linear, non-hierarchical relationships in an organisation; - Does not include customers.

MB-L4 TYPE OF OC (1)

1) TEAM BASED/HIERARCHICAL;

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MB-L4 TYPE OF OC (2)

2) MATRIX

MB-L4 TYPE OF OC (2)

3) FLAT

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EXAMPLE 1 (B-MJV) MB-L4 Administrative Council

Internal Audit Medical director Dept Quality Manager Secretariat IH Lab HR

Archive TTI Lab Accounting & Finance

Collection Lab Preparation Transport, Laboratory and procuring Dept for mobile distribution collection LP preparation Dept Dept for donor advise Technical - Dept for QC Maintenance Dept for pre- collection Dept for Distribution Public Purchasing

EXAMPLE 2 MB-L4

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MB-L4 SUMMARY/CONCLUSION

 You know everything about OC now!  OC is essential in organisation!  Basis for communication, management and setting-up a QMS……because QM is management and communication after all!  For achieving a successful QMS, the structure of the organisation should be clearly defined and this should be reflected in an OC with clear alignment of responsibilities.

MB-L4 USEFUL LINKS

 http://knowhownonprofit.org/organisation/orgdev/structure-and- culture/structure

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MANAGEMENT OF QUALITY DOCUMENTATION Module B:Processes Management - Lecture 5

Trainer: M-L Hecquet Lecture 5 –Day 2

MB-L5

TEACHING AIM

 Understand the different kind of quality documentation;  Management of the quality documentation

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REGULATIONS (1) MB-L5

Directive 2002/98/EC

Information to be provided by blood establishment to the competent authority for the purposes of designation, authorisation, accreditation or licensing in accordance with article 5(2):

- Documentation, such as an organisation chart, including responsibilities of responsible persons and reporting relationships; - Documentation such as site master file or quality manual describing the quality system in accordance with Article 11(1); - Number and qualifications of personnel; - Hygiene provisions; - Premises and equipment; - List of standard operating procedures for recruitment, retention and assessment of donors, for processing and testing, distribution and recall of blood and blood components and for the reporting and recording of serious adverse reactions and events.

REGULATION (2) MB-L5

Directive 2005/62/EC

Documents setting out specifications, procedures and records covering each activity performed by the blood establishment shall be in place and kept up to date

- Personnel and Organisation; Premises ; Equipment and Materials; Documentation; Blood collection, testing and Storage including Donor Eligibility, Collection, Laboratory testing, Processing and validation, Labelling, Release of blood and blood components; Storage; Contract Management; Non-Conformance including deviations, Complaints, Recall, Corrective and preventive actions; Self-inspection, audits and improvements

Records must be legible and may be handwritten, transferred to another medium such as microfilm or documented in a computerised system All significant changes to documents must be acted upon promptly and must be reviewed, dated and signed by a person authorised to perform this task

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REGULATION (3) MB-L5

Guide to the preparation, use and quality assurance of blood components, 17th edition

A document control system, defined in a written procedure, must be established for review, revision history and archiving of documents, including SOP.

Each activity that may affect the quality and/or safety of the blood and blood components must be described in an SOP and recorded.

The records system must ensure continuous documentation of the procedures performed, from the blood donor to the recipient, i.e. each significant step must be recorded in a manner that permits a component or procedure to be traced, in either direction, from the first step to final use or disposal.

Records must be retained for a period according to local, national or EU requirements, as appropriate.

Good Practices Guideline

Whole section 5

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QUALITY DOCUMENTS? MB-L5 WHAT DID YOU SAY?

QUALITY DOCUMENT……WHAT IS IT? - Every document that you need to write, and/or which describes in a standardised way processes, which ultimately lead to the quality of the processes and product/service ; - Every document that prove the quality of the process and product/service and show that your process is under control! A Quality Document should be an Help to reach Quality But not a Burden!

Q-DOCUMENT= SAY WHAT YOU DO

CATEGORIES OF DOCUMENTS MB-L5

I. Laws/Standard (External I II. Quality Manual -Policies and Objectives – Express the highest level of II goal/intent of the BE. III. General Procedures - Describes flow of activities, decision points, responsibilities of III departments & acceptance criteria to accomplish a given course of action  ref to specific OPs. IV. Operational Procedures- Detailed IV step by step instructions to accomplish a task. V. Supporting Documentation Worksheets, forms, templates, labels V Records to support the procedures & processes =proof) Figure 1. Structure of a controlled document system

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HOW TO START? MB-L5

Do you know why they follow me?

1. QUALITY MANAGER MB-L5

- Motivates staff;

-Buildstrust within the team;

- Leader;

- Overview of the quality management;

- Incentive to write/revise quality documents to facilitate your work and improve quality;

- Keep track of the elaboration/revision of the Q-documents.

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2. IDENTIFICATION OF STANDARDS MB-L5

 MANDATORY

- National law -EU directives - CoE Guide 17th (depending on the national law)

 NON MANDATORY (At your own discretion)

- ISO 9001, ISO 15189 -GMPs - PIC/S IMPORTANT NOTE

Quality documentation is not just a copy/paste of requirements & standards

3.1. PROCESSES MAP/CARTOGRAPHY MB-L5

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3.2. MICRO-CARTOGRAPHY FOR MB-L5 DOCUMENTATION

M2: Management of Q-Documentation

General Procedure P/M2: General procedure describing the life cycle of a quality document from elaboration to implementation Instruction (I) or Operational procedure (OP) e.g I/M2.01: Instruction for I/M2.02: Instruction I/M2.03: Instruction elaboration of a Q- « approval of a Q- « revision of a Q- Document document » document »

Forms F/M2.01: Request for new Q-document

3.2. MICRO-CARTOGRAPHY FOR MB-L5 DOCUMENTATION

M3: Management of Staff: Recruitment and training

General Procedure P/M3: General procedure describing the process of management of staff from recruitment, initial training, continuous training to end of contract

Instruction (I) or Operational procedure (OP) e.g I/M3.01: instruction for I/M3.02: instruction I/M3.03: Instruction recruitment « initial training » « continuous training »

Forms F/M3.01: Check list F/M 3.02: trainings need F/M 3.03: Assessment « new arrival » checklist of training

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IN BETWEEN SUMMARY MB-L5

Quality Manager  Leader

Organigram Responsibilities defined

Mapping processes  List of Quality Documents

Attribute the elaboration/revision of documents to the staff responsible (competent user) of the activity.

4. WRITING PHASE MB-L5

4.1. PREPARATION PHASE

- Identify the objective, scope of the document and title ; - Identify the competent user and assign responsibility for writing the document;

4.2. WRITING PHASE

-Use a model/template; - Design a process flow chart and describe each step of the work process; Think about the criticality of the process;

MORE GUIDANCE: EU-Q-SOP PROJECT

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EU-Q-SOP PROJECT: GUIDANCES MB-L5

 Template  Flowcharting

 Identification of competent users

Q-DOCUMENT: KEY POINTS MB-L5

-SOPnumber and unique number; - Title: clear and descriptive; - Version number; - Page number and total number of pages; - Name and signature of author + Signature date; - Name and signature of person who authorised the introduction of the document + Signature date; - Effective date, date on which the document/revised version become effective; - Consistent structure; - Note on the changes included.

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Q-DOCUMENT: CONTENT MB-L5

1. Objective; 2. Area of application/scope; 3. Definitions/abbreviations; 4. Roles covered by the document; 5. Description of the process or activity/logigram; 6. Related documents; 7. References to external documents/related Q-Documents; 8. Annexes.

5. DOCUMENT CHANGE CONTROL & MB-L5 IMPLEMENTATION (1)

AIM OF A DOCUMENT CHANGE CONTROL SYSTEM

 Control any changes in the life of a Q-Document: issue, revision, distribution, disposal, archiving, destruction;

 Prevent use of obsolete document.

Formal process used to ensure that changes to Q-Documents are introduced in a controlled and coordinated manner  Standardised Procedure on document change control

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5. DOCUMENT CHANGE CONTROL & MB-L5 IMPLEMENTATION (2)

1. Identification of need for a new Q-document or revision

(e.g. form to be 2. Initiate the change filled-in)

3. Approval of (e.g. approval the change form) YES 4. Registration of the document (e.g. SOPs registry)

5. Elaboration

6. Review

NO 7.Approval & signatures

5. DOCUMENT CHANGE CONTROL & MB-L5 IMPLEMENTATION (3) 7.Approval & signatures

YES 8. Make document available to users with (e.g. list of controlled an effective date and in a controlled way documents)

-Archiving of 9. Retrieve obsolete version and make it original document unavailable to personnel -Destruction of controlled copies

10. Appropriate and controlled storage (e.g. list of archived documents)

11. Appropriate Training (before effective (e.g. Training form) date)

12. Implementation (effective date)

13. Audit (e.g. Audit plan & report)

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LAST REMARKS BEFORE THE END MB-L5

- List of Q-Documents  Keep track of revision, date of revision, effective date & responsible person;

- Relevant versions of applicable documents available at points of use!

-Documents of external origin identified and their distribution controlled;

- Prevent unintended use of obsolete documents;

- Completed & Readable forms.;

- Corrections to a document/record: to be signed, initialled & dates. - Correction must permit the reading of original information - Reason for correction to be recorded, when appropriate

- Period of retention/archiving period;

SUMMARY/CONCLUSION MB-L5

 Q-Documentation shall be elaborated on a risks based approach;  It ensures that work is performed the same way  « Standardised Operating Procedure »  Proof of your work;  Traceability Purpose;  Documentation: an initial huge effort, which becomes worth in the long run.

WRITE WHAT YOU DO & DO WHAT YOU WRITE

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USEFUL LINKS/READINGS MB-L5

 EU-Q-SOP Manual - http://www.eubis europe.eu/blood_manual_details.php?ausgabe=sop

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TRAINING IN QMS

Without a well-trained workforce, high quality work becomes an impossible task Module B:Processes Management - Lecture 6

Trainer: M. v. Roosmalen Lecture 6 - Day 2

MB-L6

TEACHING AIM

 Understand the relevance of training in QMS  Be able to set up and implement a training programme

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REGULATIONS (1)

Directive 2005/62/EC – Annex 2 1. Personnel shall be available in sufficient numbers to carry out the activities […] and be trained and assessed to be competent for their tasks. 2. Personnel shall have up to date job descriptions which clearly set out their tasks and responsibilities. 3. Personnel shall receive initial and continued training appropriate to their specific tasks. Training records shall be maintained. Training programmes shall be in place and shall include good practice. 4. The contents of training programmes shall be periodically assessed and the competence of personnel evaluated regularly.

REGULATIONS (2) MB-L6

Guide to the preparation, use and quality assurance of blood components, 17th edition

References to EU Directive 2005/62/EC

And multiple references in several chapters:

Qualification: ……the calibration, cleaning, preventative maintenance, operating procedures and operator training procedures and records should be documented. Documentation: Procedures should be designed, developed and validated, and personnel should be trained, in a consistent manner.

Good Practice Guidelines

References to EU Directive 2005/62/EC Training should be provided for all personnel whose duties take them into preparation area or into laboratories.

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REGULATIONS (3) MB-L6

EU GMP – Chapter 1 There are competent and appropriately qualified personnel in sufficient numbers. Senior management should provide adequate resources. The responsibilities of all staff should be clearly understood and recorded. All personnel receive initial and continuing training relevant to their needs. Practical effectiveness should be assessed periodically Only trained staff are authorised to carry out that procedure/enter certain areas. Training should be structured and continuous. Training records should be kept Training programmes should be available

REGULATIONS (4) MB-L6

PICS/S for Blood establishments There should be an adequate number of personnel. The responsibilities of personnel should be described. There should be an organisation chart showing the hierarchical structure of the BE. Personnel should receive initial and continuous training to ensure that they have the skills to perform their assigned tasks. Records should be maintained to demonstrate compliance to training requirements. The effectiveness of the programmes should be regularly assessed. Personnel should have relevant knowledge of basic transfusion medicine, microbiology, hygiene and GMP. Personnel in key areas of responsibility should have appropriate qualifications, experience, and specific training to discharge their responsibilities. Delegation should only be given to appropriately qualified and authorised individuals who have been trained for the task. Delegation should be in written form.

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WHY IS TRAINING IMPORTANT? (1) MB-L6

ORGANISATION - Fundamental to quality and safety; - To ensure good process control (less variation); - Higher employee satisfaction/morale  Team Spirit  same goals.

INDIVIDUAL -Increased knowledge and skills; -Increased awareness of responsibilities within the process.

WHY IS TRAINING IMPORTANT? (2) MB-L6

The organisation benefits from having a skilled and motivated workforce: - Improved quality, reduced errors; - Fewer safety/quality incidents/NC; - Less equipment damage; - Less complaints; - Higher efficiency; - Increased production; - Cost-reduction.

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GOOD TRAINING = A MAJOR MB-L6 CHALLENGE

An indicator for the extent of this challenge can be withdrawn from analysing the type and ranking of FDA findings: - For biologics the most frequent causes of findings (105/191): procedures not always maintained and followed (data taken from: www.fda.gov/ICECI/Inspections (2013); - Data  compliance with procedures and documentation are major source for findings;  For the stability of the QMS, the success of training is very important.

PERSONAL AWARENESS MB-L6

- Personnel in regulated environment need to know why they have additional demands placed upon their performance; - The reason should go beyond “ because you have to…, it’s the law”; - Without a personal value for (GMP) compliance, a compliant operation will be very difficult to achieve!; - Value must come from the realisation that: - they need to ensure the blood quality and safety and; - that each individual performance has the potential to affect this.

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MB-L6 RESPONSIBILITIES FOR TRAINING

Develop organised training programme that includes: - Employees are trained for the tasks they perform; - Developed training programme comprising: - Training/Qualification of new employees; - Re-Qualification of existing employees; - Training identification, prioritisation and schedule (WHO should be trained, on WHICH tasks/job, by WHEN (date) and HOW); - Assessment of training effectiveness; - Documentation/recording: Training procedure for initail and continuous training, training plan/programmes, training content, assessment; - Improvement, when necessary.

TRAINING PROCESS MB-L6

Training needs & Develop training Training Training requirements Programme Implementation Evaluation Authorisation assessment

TRAINING DOCUMENTATION

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STEP 1. ASSESS MB-L6

Training needs & requirements assessment

TRAINING DOCUMENTATION

-Review job requirements (job description!); - New and existing employees (experience, background); -Identify the categories of staff; -Perform tasks analysis of job (through interview, direct observation); - Identify required skills to perform the job; - Determine gap between current and required skills; -Define level of competence for each job function; -Regulatory requirements (hygiene, GMP).

STEP 2. DEVELOP MB-L6

Training needs & requirements Develop training assessment Programme

TRAINING DOCUMENTATION

- Allocate resources (budget, time of personnel to be trained, trainers, equipment, space, materials); -Define who and what should be included in the training; - Define purpose, outcome objectives; - Decide on training content / method; - How will the competence be evaluated; - Determine criteria for certification; -Define validity; -Design forms for recordkeeping of training; -Define qualifications of the trainer.

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EXAMPLE MB-L6

OUTCOME CONTENT METHOD EVALUATION CERTIFICATI OBJECTIVE (measurable ON behavior to outcome objective) 1. Operate the References Review SOP Employee … A minimum of 5 processing SOP times in centrifuge Operator’s Manual Show centrifuge Successfully succession under parts performs observation by an Topics operation of experienced staff Centrifuge parts Use SOP to centrifuge member who has Time practice according to SOP been identified as Temperature trainer Balance Program Troubleshooting

STEP 3. IMPLEMENT MB-L6

Training needs & requirements Develop training Training assessment Programme Implementation

TRAINING DOCUMENTATION

- Training material had been developed; - Validate training (try-out in small group) and revise training if necessary; - Develop an agenda; - Schedule days, times, places; - Schedule trainings, trainers, personnel.

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STEP 4. EVALUATE MB-L6

Training needs & Develop training Training requirements Training Evaluation Authorisation Programme Implementation assessment

TRAINING DOCUMENTATION

- What is evaluated: - Components and process ; -Transfer of knowledge (written test, performance of practical exercises, observation); - Trained personnel: achievement of objectives, feedback; - Trainer: organisation, feedback of personnel; - Manager: effectiveness of return on training investment. Feedback used to increase quality and effectiveness of training!

LONG TERM EVALUATION MB-L6

Standards/Requirements-related performance compared BEFORE and AFTER training - Product failures; - Non-conformities statistics; - Audit results; -Operational efficiency.

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DOCUMENTATION/ RECORDS MB-L6

Training needs & Develop training Training Training requirements Programme Implementation Evaluation Authorisation assessment

If not documented: it is not done ! - Assessment of training needs of employees; - Training plan; - Training sheet: Employee name, department name, trainer’s name, training date; - Attendance list; - Evaluation sheets; Competences/knowledge areas successfully completed (specific training course, SOP); - Sign off training/qualification by employee, trainer and manager  Authorisation; - Keep records and make sure it remains up-to-date; - List employees authorised for a specific job and those who still need to take/ renew training  DATABASE WITH ALL INFO

RECORD SOP TRAINING: EXAMPLE MB-L6

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TRAINING – DEVELOPMENT CYCLE MB-L6

DESIGN

ASSESS IMPLEMENT

EVALUATE

SUMMARY/CONCLUSION MB-L6

 Training is essential for promoting and establishing a QMS;

 Despite potential drawbacks (time, resources), training provides both the organisation & employees with benefits that make cost and time a worthwhile investment.

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USEFUL LINKS/READINGS MB-L6

 http://www.who.int/bloodsafety/publications/qmp_toolkit/en/

Page 93 12 MODULE C- SUPPORT PROCESSES

15 April 2015 - Lecture 7, Risk in Perspective, A. Aquilina - Lecture 8, Introduction to Risk Management Tools, J. Ceulemans - Lecture 9, Qualification: A Risk-based Approach, A. Aquilina

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RISK IN PERSPECTIVE ModuleProcesses - C: Lecture 7 Support

Trainer: A. Aquilina Lecture 7 –Day 2

MC-L7

TEACHING AIM

 Understand Risk Management;  Why is it important to manage/assess risks.

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DEFINITIONS (1) MC-L7

RISK DEFINITION: « Effect of uncertainty on objectives » RISK MANAGEMENT DEFINITION: something that “ aids decision making by taking account of uncertainty and its effect on achieving objectives and assessing the need for any actions” (ISO 31 000:2009- « Risk management—Principles and guidelines on implementation)

DEFINITIONS (2) MC-L7

RISK DEFINITION: « The combination of the probability of occurrence of harm and the severity of harm » QUALITY RISK MANAGEMENT DEFINITION: « A systematic process for the identification, assessment and control of risks to the quality of pharmaceutical product across the product lifecycle »

(ICH Q9 - « Quality Risk Management”)

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APPLICATION TO THE BLOOD FIELD MC-L7

RISK IN BLOOD TRANSFUSION Probability of the occurrence of a ultimate harm on the donor/recipient and its severity

RISK MANAGEMENT Eliminate or minimise the occurrence of this harm and the severity of the harm on the donor/recipient

LET’S START WHO HAS AN EXAMPLE OF RISK IN THE BLOOD FIELD?

EXAMPLES PLEASE? MC-L7 Monitoring & Management & Realisation/Core activities Support Improvement Documentation Audits Donor Human Selection Complaints resources management Haemovigilance Blood Equipment Collection Deviations management Recalls

Qualification/ Processing Testing Management Validation review

Material CAPA management Release

Supplier control Storage

Financial Transport management

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RISK MANAGEMENT IS NOT NEW! MC-L7

But implicit?

Directive 2002/98/EC

“Premises including mobile sites shall be adapted and maintained to suit the activities to be carried out. They shall enable the work to proceed in a logical sequencesoasto minimise the risk of errors, and shall allow for effective cleaning and maintenance in order to minimise the risk of contamination.”

“Blood collection procedures shall minimise the risk of microbial contamination”.

EU GMP – Annex 15 – Qualification and Validation

“A risk assessment approach should be conducted to determine the scope and extent of validation”

IMPORTANCE OF RISK MANAGEMENT MC-L7

USEFUL TOOL TO: - Implement, maintain and continuously improve a QMS in a resource effective manner; -Create awareness and influence the factors/hazards; - Critical processes are under control; provide thus confidence; - Incentive to implement preventive actions; - Recognise risks at desired level  zero risk does not exist.

RISK MANAGEMENT IS A DISCIPLINE

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RISK MANAGEMENT PROCESS (1) MC-L7

Initiate QRM Process

Risk identification

Risk Analysis

Risk Evaluation Risk Assessment

Risk Reduction unacceptable

Risk Risk Acceptance Control COMMUNICATION

Output/result of the QRM Process RISKS TOOLS MANAGEMENT

RISK MANAGEMENT TOOLS (2) MC-L7

Initiate QRM Process Identify the source of risks: Brainstorming, Cause & Effect assignements (Fishbone/Ishikawa), Risk identification Flow charts, Fault tree analysis,

Risk Analysis Analyse the causes and source of risks and the likelihood to occur Risk Evaluation Risk Ranking, FMEA, FMECA

Risk Assessment HACCP

Determine whether risks to be adressed/treated Risk Reduction Determine Strategies to

Risk Risk Acceptance mitigates/control the risk Control SPC, Process sensors, indicators RISKS TOOLS MANAGEMENT

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RISK MANAGEMENT PROCESS (3) MC-L7

REDUCTION, ACCEPTANCE, WHAT MC-L7 ELSE ? Consider also…….

Avoiding Risks - Why installing a temperature sensitive automate in a area known as being hot and where no air conditioning can be installed?

Transfer Risks - Outsourcing of testing

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MC-L7

SUMMARY/CONCLUSION MC-L7

 QRM does not eliminate risks but is a tool to manage them (identification/assessment/monitoring/prioritisation…..)  RM is a discipline  Focus not on objectives but on the risks to achieve the objectives  4Ps: Proactive-Preventive-Predictive-Preemptive

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USEFUL LINKS/READINGS MC-L7

 http://www.ich.org/products/guidelines/quality/q9-briefing-pack.html http://www.researchgate.net/publication/229602150_Quality_risk_ma nagement_a_valuable_tool_in_implementing_maintaining_and_improv ing_a_quality_management_system (Agoston et. Al, ISBT Science Series (2011) 6, 52-55)

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INTRODUCTION TO RISK MANAGEMENT TOOLS ModuleProcesses - C: Lecture 8 Support

Trainer: J. Ceulemans Lecture 8–Day 2

MC-L8

TEACHING AIM

 Understand basic tools for risk management;  Aid to get more knowledge;  Be able to use tools.

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METHODS AND TOOLS MC-L8

 Guidance;  Tools to be adapted to the risks/to every situation  No one tool is « all inclusive »!  The list provided is not exhaustive.

METHODS & TOOLS - OVERVIEW MC-L8

1. Initiate QRM Process Identify the source of risks: Brainstorming, Cause & Effect assignements (Fishbone/Ishikawa), 2. Risk identification Flow charts, Fault tree analysis, Mind Map 3. Risk Analysis Analyse the causes and source of risks and the likelihood to 4. Risk Evaluation occur

Risk Assessment Risk Determine whether risks to be adressed/treated Risk Ranking, FMEA, FMECA HACCP 5. Risk Reduction Determine Strategies to mitigates/control the risk Risk 6. Risk Acceptance

Control SPC, Process sensors, Indicators RISKS TOOLS MANAGEMENT

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1 INITIATION QRM MC-L8

ALLOCATE RESPONSABILITIES & INITIATE QRM 1.1. Interdisciplinary team – experts from appropriate areas (Quality unit, production, legal…and experts knowledgeable about risk) 1.2. Decision Makers - Take responsability for the coordination of the QRM 1.3. Initiate - objectives, define problem/risk question - assemble background information/define the context - develop a plan, timeline, deliverables - records to be kept

2 RISK IDENTIFICATION (1) MC-L8

QUESTION: WHAT MIGHT GO WRONG?

Use of information (Historical data, theoretical analysis, concerns of Hospitals); Identification of possible consequences; Identification of possible causes;

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2 RISK IDENTIFICATION (1) MC-L8

TOOLS FOR RISK IDENTIFICATION

BRAINSTORMING: Internal and external brainstorming (involvement of suppliers, subcontracting parties)

ISHIKAWA:

Problem Statement = Risk + Policies Causes + Procedures + Plant + Budget/Cost MIND MAP

2 RISK IDENTIFICATION (2) MC-L8

ISHIKAWA – EXAMPLES 1. RISK= delayed flight departures

2. RISK= Tea not available during the training course break

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2 RISK IDENTIFICATION (3) MC-L8

MIND MAP – EXAMPLE PROCESS MAPPING – EXAMPLE

Donor Selection Causes Blood Collection

Processing Testing

Release

Storage

Transport

3 & 4 RISK ANALYSIS & EVALUATION (1) MC-L8

TOOLS RISK RANKING SEVERITY Quantitative LIKELYHOOD

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3 & 4 RISK ANALYSIS & EVALUATION (2) MC-L8

TOOLS RISK RANKING Qualitative SEVERITY LIKELYHOOD

3 & 4 RISK ANALYSIS & EVALUATION (3) MC-L8

TOOLS FAILURE MODE EFFECTS ANALYSIS (FMEA) - SEVERITY – Table in Annex - PROBABILITY - Table in Annex - DETECTION - Table in Annex

Potential Failure Potential effect Potential Item/Process SP D RPN Cause of failure Causes 1. Set up of an Insufficient Fail to start Cleaning 4 5 8 160 automate cleaning of procedure equipment not up to date 4x5x8 = 160 Recommended Action S P D RPN Change cleaning procedure 4 3 4 48

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5& 6 RISK CONTROL (1) MC-L8

DECISION MAKING -To reduce/accept risk to an acceptable level; - Benefit/cost analysis; - Amount of effort used for risk control proportional to the significance of the risk.

QUESTIONS: - Is the risk above an acceptable level? - What can be done to reduce or eliminate the risk? - What is the appropriate balance among benefits, risks and resources?

5& 6 RISK CONTROL (2) MC-L8

RISK REDUCTION -Action to mitigate severity and probability of harm; - Processes that improve detectability of risks;  Are new risks introduced as a result of the identified risks being controlled?  New risks  Risk Assessment RISK ACCEPTANCE - Decision to accept the risk and residual risks .

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5& 6 RISK CONTROL (3) MC-L8

TOOLS STATISTICAL CONTROL - Control charts - Pareto charts

QUALITY INDICATORS e.g. number of non-conformities for a given process

PROCESS SENSORS e.g. Temperature data logger

SUMMARY/CONCLUSION MC-L8

 Various tools for Quality Risk Management;  Adapt tools to the situation;  Combination of tools is possible:  Quality Risk Management: pro-active approach for identifying and controlling quality issues.

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USEFUL LINKS/READINGS MC-L8

 http://www.ich.org/products/guidelines/quality/q9-briefing-pack/briefing- pack.html

MC-L8

Risk Controlled Mountain Bike Riding

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ANNEX 1 MC-L8

FMEA - Occurrence Rating Scale Rating Description Potential Failure Rate 10 Very High: Failure is More than one occurrence per day or a probability of more than three almost inevitable. occurrences in 10 events. 9 High: Failures occur One occurrence every three to four days or a probability of three almost as often as not. occurrences in 10 events . 8High: Repeated failures. One occurrence per week or a probability of 5 occurrences in 100 events . 7High: Failures occur One occurrence every month or one occurrence in 100 events . often. 6 Moderately High: One occurrence every three months or three occurrences in 1,000 events . Frequent failures. 5 Moderate: Occasional One occurrence every six months to one year or five occurrences in failures. 10,000 events . 4 Moderately Low: One occurrence per year or six occurrences in 100,000 events . Infrequent failures. 3 Low: Relatively few One occurrence every one to three years or six occurrences in ten million failures. events . 2 Low: Failures are few One occurrence every three to five years or 2 occurrences in one billion and far between. events . 1 Remote: Failure is One occurrence in greater than five years or less than two occurrences in unlikely. one billion events .

ANNEX 2 MC-L8

FMEA – Severity Rating Scale

Rating Description Definition (Severity of Effect) 10 Dangerously high Failure could injure the customer or an employee. 9 Extremely high Failure would create noncompliance with federal regulations.

8 Very high Failure renders the unit inoperable or unfit for use. 7 High Failure causes a high degree of customer dissatisfaction. 6 Moderate Failure results in a subsystem or partial malfunction of the product.

5 Low Failure creates enough of a performance loss to cause the customer to complain. 4 Very Low Failure can be overcome with modifications to the customer’s process or product, but there is minor performance loss.

3 Minor Failure would create a minor nuisance to the customer, but the customer can overcome it without performance loss. 2 Very Minor Failure may not be readily apparent to the customer, but would have minor effects on the customer’s process or product.

1 None Failure would not be noticeable to the customer and would not affect the customer’s process or product.

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ANNEX 3 MC-L8

FMEA – Detectability Rating Scale

Rating Description Definition 10 Absolute Uncertainty The product is not inspected or the defect caused by failure is not detectable.

9 Very Remote Product is sampled, inspected, and released based on Acceptable Quality Level (AQL) sampling plans. 8 Remote Product is accepted based on no defectives in a sample. 7 Very Low Product is 100% manually inspected in the process. 6 Low Product is 100% manually inspected using go/no-go or other mistake-proofing gauges. 5 Moderate Some Statistical Process Control (SPC) is used in process and product is final inspected off-line. 4 Moderately High SPC is used and there is immediate reaction to out-of-control conditions.

3 High An effective SPC program high. 2 Very High All product is 100% automatically inspected. 1 Almost Certain The defect is obvious or there is 100% automatic inspection with regular calibration and preventive maintenance of the inspection equipment.

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QUALIFICATION: A RISK BASED APPROACH ModuleProcesses - C: Lecture 9 Support

Trainer: A. Aquilina Lecture 9 –Day 2

MC-L9

TEACHING AIM

 Understand the concept of qualification and validation;  Understand the qualification/validation cycle;

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QUALIFICATION MC-L9

- For the inspector?

- For the Quality Manager?

- For the patient?

Qualification is not for the Inspector or the Quality Manager it is FOR SAFETY REASONS (PATIENT & DONOR )

DEFINITIONS MC-L9

QUALIFICATION DEFINITION: “Provision of evidence that a specific equipment, facility or system is fit/ready for intended use/that predefined requirements for a specific equipment, facility or system are fulfilled” (Own definition)

VALIDATION DEFINITION: “Provision of evidence that requirements for a specific intended use are fulfilled” (ISO 9000:2005) “Provision of objective evidence that pre-defined requirements for a specific procedure or process can be consistently fulfilled” (CoE Guide)

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POLICY MC-L9

Computer Equipment / Process Assays Systems Infrastructure

Serological Production Software Premises assays

Molecular Transport Biological Hardware Equipment assays

Quality control Disinfection Fixes, Updates Systems assays

Process Method Computer system Qualification validation validation validation

REGULATIONS MC-L9

Guide to the preparation, use and quality assurance of blood components, 17th edition All validated processes must use qualified equipment. Qualification results must be documented. Facilities and equipment need to be qualified prior to implementation. Systems, processes and tests all need to be validated.

EU-GMP Critical steps of manufacturing processes and significant changes to the processes are validated. (e.g. Annex 15: Qualification and Validation in revision)

PICS/S for Blood establishments Equipment for collection, preparation and storage of blood and blood components should be dedicated to its use. New and repaired equipment should meet qualification requirements when installed and authorised before use. Qualification results should be documented.

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GENERAL PROCEDURE MC-L9

Definitions: Formal documentation URS: User requirements specification URS: separate document RA: risk assessment has to be documented RA: Risk assessment DQ: Design qualification DQ, IQ, OQ, PQ: IQ: Installation qualification • Plan: Definition of acceptance criteria's, test OQ: Operational qualification procedures PQ: Performance qualification • Records: raw data ReQ: Re-Qualification • Report: Evaluation whether criteria's are met, deviations, changes to the test plan • All documents have to be approved by QM

EXAMPLES MC-L9

Example 1 Example 2

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URS (USER REQUIREMENT MC-L9 SPECIFICATION) / LASTENHEFT

The URS defines the specifications for your equipment /premises. The URS is your reference document throughout the qualification life cycle.

Example 1: Example 2:

URS - EXAMPLES MC-L9

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RISK ASSESSMENT MC-L9

The risk assessment helps to define the critical elements of your equipment and to establish the qualification parameters. The risk assessment defines the content of the qualification.

Possible general risk bases approach: • Each equipment is categorised with predefined qualification parameters

MC-L9

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DESIGN QUALIFICATION MC-L9

DEFINITION: The documented verification that the proposed design of the facilities, systems and equipment is suitable for the intended purpose.

During the DQ the compliance of design with your specifications and GMP is demonstrated and documented.

Example 1: Example 2: • Floor plan with details • Offers from builders with indications for the materials planned to be used, installations, alarms • Technical documentation (wiring, P&ID Schema)

INSTALLATION QUALIFICATION MC-L9

DEFINITION: The documented verification that the facilities, systems and equipment, as installed or modified, comply with the approved design and the manufacturer’s recommendations

During the IQ the verification of the correct installation is performed Example 1: Example 2: • Verification of construction (no damages, correct materials used, doors are tight, …) • Temperature- and alarm- monitoring correctly installed • Operating and working instructions are available • Calibration of sensors

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OPERATIONAL QUALIFICATION MC-L9

DEFINITION: The documented verification that the facilities, systems and equipment, as installed or modified, perform as intended throughout the anticipated operating ranges.

During the OQ the verification of the correct function is performed

Example 1: Example 2: • Equipment file and SOP is available including cleaning procedures • Temperature monitoring: empty, loaded (with monitoring including hot spots, cold spots) • Alarm system testing • Open door tests • Shortage of power B-QM WG©2015 EDQM, Council of Europe. All rights reserved. Training Course - April 2015 15

PERFORMANCE QUALIFICATION MC-L9

DEFINITION: The documented verification that the facilities, systems and equipment, as connected together, can perform effectively and reproducibly, based on the approved process method and product specification.

During the PQ the verification of the correct function during routine conditions is performed.

Example 1: Example 2: • Temperature monitoring during one week under real conditions • Alarm monitoring: False alarms?

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VALIDATION MASTER PLAN (VMP) MC-L9

- All qualification and validation activities should be planned and take the life cycle of equipment, process and product into consideration; - Validation activities to be performed by suitably trained personnel; - The key elements of the site validation programme should be clearly defined and documented in a validation master plan (VMP) or equivalent document. - Validation policy; - Organisational structure of validation activities; - Summary of the facilities, systems, equipment, processes on site and the current validation status; - Template formats to be used for protocols and reports; - Planning & scheduling; - Change control; - Acceptance criteria; - Reference to existing documents; - Resources required.

SUMMARY/CONCLUSION MC-L9

 Qualification of equipment in blood establishments should be seen as an excellent tool to gain confidence in your equipment and procedures rather than a burden;  A risk based approach can standardise and minimise your qualification work to a useful and reliable extend;  Sample size to be based on statistical rationale;  Qualification is not for the Inspector or the Quality Manager.

It is

FOR SAFETY REASONS (PATIENTS / DONORS)

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USEFUL LINKS/READINGS MC-L9

 GMP Annex 15 - http://ec.europa.eu/health/files/gmp/2014- 02_pc_draft_gmp_annex.pdf

ISBT Guidelines for Validation of automated Systems in Blood Establishments http://www.isbtweb.org/fileadmin/user_upload/guidelines-Validation- Automated-Systems-in-Blood-Establishments.pdf

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MODULE D- REALISATION PROCESSES

16 April 2015 - Lecture 10, Key Performance Indicators in Blood Establishments, J. Ceulemans - Lecture 11, Quality Control & Statistical Process Control, J. Ceulemans/A. Aquilina

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KEY PERFORMANCE INDICATORS IN BLOOD

ESTABLISHMENTS Module D:Processes - Lecture Realisation 10

Trainer: Jan Ceulemans Lecture 10 – Day 3

MD-L10

TEACHING AIM

 Introduction to KPI;  Sensitisation to the use of KPI.

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MD-L10 KPI

Key Performance Indicator Helps an organisation define and measure progress toward organisational goals; Quantifiable measurements, agreed to beforehand, that reflect the critical success factors.

STRATEGIC PLAN MD-L10

Strategic Plan

Action Plans Mission Why we exist Evaluate Progress Vision What we want to be

Goals What we must achieve to be successful

Objectives O1 O2 Specific outcomes expressed in measurable terms (NOT activities) Planned Actions to Initiatives AI3 AI1 AI2 Achieve Objectives

Indicators and Measures M1 M2 M3 Monitors of success Targets T1 T1 T1 Desired level of performance and timelines

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MEASUREMENTS MD-L10

- Measure your milestones – short-term outcomes at Action Item level; -Measure the outcomes of your objectives; - Try to keep your measures one per objective; - May want to include lead and lag measures to depict cause-effect relationships if you are uncertain about driving (leading) the desired outcome; - Establish measures using a template to capture critical data elements.

EXAMPLES OF MEASUREMENTS MD-L10

Average time Better to initiate Shorter time customer customer service contact:

Average Below Increased response average effectiveness time to response in dealing incident: times with incident

Facilities that meet improved operational facility quality A1 readiness for meeting rating customer needs

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TARGETS MD-L10

- For each measurement, at least one target; - Bring the organisation to higher levels of performance; - Incremental improvements over current performance; - Put focus on your strategy; - Successfully executed your strategy when targets reached; - KPI need to be smart: - Specific; - Measurable; - Achievable; - Realistic; - Time based.

EXAMPLES OF TARGETS MD-L10

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MD-L10 SANITY CHECK

Make sure everything is linked and connected for a tight end-to-end model for driving strategic execution.

OBJECTIVE Improve Employee Satisfaction

MEASURE / TARGET 90% Measure Employee Satisfaction gap INITIATIVE Survey 45% ACTION PLAN Rating Employee Identify issues per a Productivity company wide Target 90% Satisfaction Percent Improvement survey favorable Program overall Target Actual

SUMMARY /CONCLUSION MD-L10

 Help to measure organisational performance;  Help to measure process performance;  KPI linked to organisational goals;  Focus on a few critical KPI rather than on many trivial ones.

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MD-L10

Page 130 6 01/02/2019

QUALITY CONTROL & STATISTICAL PROCESS CONTROL Module D:Processes - Realisation Lecture 11

Trainer: J. Ceulemans/A. Aquilina Lecture 11 –Day 3

MD-L11

TEACHING AIM

 Learn more about Quality Control (QC) and Statistical Process Control (SPC);  Understand the value of SPC;

Page 131 1 01/02/2019

DEFINITIONS MD-L11

QUALITY CONTROL DEFINITION: « part of a quality system focussed on fulfilling quality requirements » (Directive 2005/62/EC) STATISTICAL PROCESS CONTROL DEFINITION: « Tool that enables an organisation to detect changes in the processes and procedures it carries out by monitoring data collected over a period of tile in a standardised fashion » (CoE Guide/Appendix 3) « Statistical process control’ means a method of quality control of a product or a process that relies on a system of analysis of an adequate sample size without the need to measure every product of the process » (Directive 20004/32/EC)

REGULATIONS (1) MD-L11

Directive 2005/62/EC

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- conformance and self-inspection.

CoE guide (Blood components Monographs)

- Quality Control Requirements

- Frequency of sampling for all measurements shall be determined using statistical process control

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REGULATIONS (2) MD-L11

CoE Guide & Good Practice Guidelines What does Quality Control encompass? - Defined specifications - Validation of QC procedures - QC Results evaluated, Statistical Process Control - Standard procedure/documentation for QC in place - QC according to a Sampling plan - Assays in accordance with kit instructions - Proficiency testing scheme (PTS) - Records

REGULATIONS (3) MD-L11

EU-GMP Guide, Part 1, Chapter 6 Quality control - General (Responsibilities, Personnel) - Good Quality Control Laboratory (GQCL)Practices - Documentation - Sampling - Testing - (on-going stability programme) - (technical transfer of testing methods)

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HOT TOPICS IN QC MD-L11

Validation of QC • CE–marked kits methods • Not CE-marked kits

Sampling • Sampling plan

Out-Of- • What is an OOS? Specification (OOS) • OOS investigation

VALIDATION OF QC METHODS MD-L11

CASE 1: QC METHOD IS CE-MARKED Testing with CE-marked assays should be done according to manufacturers recommendations/instructions - Validation approach - Eligibility of the method in your laboratory • Different technicians • Different days • Different lots of the kits • Different equipments (if applicable) • …

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VALIDATION OF QC METHODS MD-L11

CASE 2: QC method is an in-house assay (non CE-marked assays) - The testing should comply with the ICH guidance Q2B „Validation of analytical methods: Methodology“(CPMP/ICH/281/95) - Validation approach

SAMPLING MD-L11

SAMPLING PLAN - Standardised Procedure describing: - The method of sampling; - The amount of samples to be taken (frequency, blood bag system…); - Instructions for any sub-division of the sampling (if required); - Identification of the containers sampled (or the segment); - Storage conditions; - Samples should be representative: - Maybe include samples for critical steps (after starting a new process, equipment, …)

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OOS (1) MD-L11

OUT OF SPECIFICATION (OOS) Product Quality Control Results  outside of the given specification, = OOS - Each OOS needs an investigation: - Laboratory; -Production. - The investigation summaries the root cause of an OOS: - Laboratory failure (retesting); - Sampling failure (resampling, reanalysing); - Production failure (material, processing, storage, …); - Others root causes;

OOS (2) MD-L11

OUT OF SPECIFICATION – LABORATORY INVESTIGATION - Investigation about the sample and the sampling; - Investigation of the testing procedure; - Method validated? - Equipment qualified? - Internal controls valid? - Staff trained? - Reagents and references ok?..... -If no failure in the testing is found  OOS-result is confirmed; - If a testing failure is found, a retesting might be conducted (Need Q- approval)

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OOS (3) MD-L11

OUT OF SPECIFICATION CONFIRMED – QUALITY INVESTIGATION - Donation process; - Transport process; - Processing process; - Material and equipment; - Qualification, training, maintenance …; - Trends, malfunctions…

Responsible person has to decide about the release of an OOS- product!

STATISTICAL PROCESS CONTROL (SPC) MD-L11

CoE Guide Appendix 3 AIM - Is my process stable? - Free of confounding factors? -I recognise trends and changes in advance and can react! - Pre-requisites: - Commitment of staff and training; - Representative sampling (statistical sampling and frequency); -Knownspecifications.

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ZOOM ON SPC SAMPLING MD-L11

NUMBER AND FREQUENCY -Trigger an appropriate response (e.g. investigation or re-validation) - Tolerance of failure: Target failure rate (failure rate that should not be exceeded); e.g. maximum 5% of RBC with residual WBC content above the limit (<5.0 x 106); - Confidence level; e.g. 95 %, 95 %Chance that QC testing will detect the problem - Frequency based on complexity of the system e.g. - Number of sites, operators; - Number of collection/processing system; - Use of multiple reagents lots; - Donor related variables; - Public health issues;Overall production volume; Risk based sampling

METHODS –EXAMPLE 1: CONTROL MD-L11 CHART (1)

Control chart maps samples of a product characteristic over time to identify when a process might be out of control

Upper and lower control values

Central line= average value

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METHODS –EXAMPLE 1: CONTROL MD-L11 CHART (2)

Control chart, but - Statistically are 3 of 1000 results out of 3 SD within a controlled process; - The probability of a “3 SD” result is 0.27% (rare event);

Different kinds of charts - Run chart - Documentation of results over time, without specification; - Control charts - Limits are based on statistical and representative data.

DECISION RULES FOR OUT OF CONTROL MD-L11 OR NON RANDOM CONDITIONS (1)

CoE Guide - Appendix 3 - Rules - Occurrence of a changes:

- Any point outside of control limits - 7 consecutive points all above/below the average line - 7 consecutive points all increasing/decreasing

WECO Rules – Distinguish unnatural patterns from natural patterns - The absence of points near the centerline (identified as a mixture pattern); - The absence of points near the control limits (identified as a stratification pattern); - The presence of points outside the control limits (identified as an instability pattern); - Other unnatural patterns (systematic (auto correlative), repetition, trend patterns

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DECISION RULES FOR OUT OF CONTROL MD-L11 OR NON RANDOM CONDITIONS (2)

WECO RULES The zone rules are designed to detect process instability. There are four basic rules that deal with appraising runs of observations within the various zones:

DECISION RULES FOR OUT OF CONTROL MD-L11 OR NON RANDOM CONDITIONS (3)

WECO RULES

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METHODS – EXAMPLE 2: SCAN MD-L11 STATISTICS

- Suitable model for determining frequency of control testing; - Determine the number of non-conforming test results in a fixed sample size - Sample = window of observations moving progressively

Example - Allowed failure rate for a conforming process: 0.1% - 1200 tests/year (100 tests/month) - Moving window of 120 consecutive tests  non-conform process if at least 3 non-conform results - False positive rate: 0.7%

METHODS –EXAMPLE 2: SCAN MD-L11 Minimum failure rate of a non-conforming process STATISTICS detectable at > 80% power in any single “window” Allowed failure Allowed failure a for rate conforming process Number of tests (e.g. the in “universe” number oftests per year) the (i.e. size Sample tests of number fixed “window”) in a moving Maximum allowed number offailed tests in window testpositive of False rate criterion Minimum “target failure rate” fornon- a conformin gprocess Power to detect non- conforming process in window any of quality tests control 30 16 2.5% 63% 81.9% 400 25% 60 26 2.9% 50% 81.7% 30 17 2.0% 66% 81.3% 1 200 60 27 3.8% 52% 83.0% 30 9 3.5% 40% 82.4% 400 10% 60 14 2.7% 30% 83.8% 1 200 30 10 2.8% 43% 81.1% 30 6 3.7% 29% 81.0% 400 5% 60 9 2.3% 21% 83.7% 1 200 30 7 2.2% 33% 82.3% 30 3 1.0% 18% 81.4% 400 1% 60 4 0.9% 11% 80.3% 1 200 60 4 2.7% 11% 80.3% 30 1 1.1 % 10% 81.6% 400 60 1 2.0% 5% 80.8% 0.1% 30 1 3.2% 10% 81.6% 22 1 200 120 2 0.7% 4.6% 80.7%

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SUMMARY/CONCLUSION MD-L11

 Performance of QC are a requirement  Ensure process are under control and product of quality  SPC allows to think upstream any changes/potential deviations might happen  SPC can show how an improvement to a process has achieved a desired result  SPC enables decision making based on rational/scientific basis

USEFUL LINKS/READINGS MD-L11

 Appendix 3 (SPC) - Guide to the preparation, use and quality assurance of blood components

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MODULE E- CONTINOUS IMPROVEMENT PROCESSES

17 April 2015 - Lecture 12, Management of Non-conformities, M.-L. Hecquet - Lecture 13, Change Control, M. v. Roosmalen - Lecture 14, Haemovigilance, B. Rothe - Lecture 15, Internal Audit, J. Ceulemans - Lecture 16, Management Review, A. Dobrota

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MANAGEMENT OF NON

CONFORMITIES ModuleImprovement – A: Lecture 12 Continuous

Trainer: M-L Hecquet Lecture 12 –Day 3

ME-L12

TEACHING AIM

 Understand the concept of NC/CAPA Management;  Be able to perform a root cause analysis  Be able to implement an action plan

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REGULATIONS ME-L12

Directive 2005/62/EC

Annex 9.1, 9.2 & 9.3 about deviations, complaints and recall

Annex 9.4. A system to ensure CAPA on blood component non-conformity and quality problems shall be in place. Data shall be routinely analysed to identify quality problems that may require corrective action or to identify unfavourable trends that may require preventive action.Allerrors and accidents shall be documented and investigated in order to identify system problems for correction.

Good Practices Guidelines

As in the Directive

EU GMP – Chapter 8 –Complaints and Recall

ISO 9001 – Chapter 8.5 Improvement

The organisation shall continually improve the effectiveness of the QMS through the use of the quality policy, objectives, audit results, analysis of data, corrective and preventive actions and management review.

DEFINITIONS ME-L12

NON-CONFORMANCE DEFINITION: « Non-fulfillment of a requirement » CORRECTION DEFINITION: « Action to eliminate a detected non-conformity » e.g. repair,reworkoradjustement CORRECTIVE ACTION DEFINITION: « Action to eliminate the cause of an existing non- conformity » PREVENTIVE ACTION DEFINITION: « Action taken to eliminate the cause of a potential non- conformity (ISO 9000:2005)

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CORRECTION, CA OR PA? ME-L12

 Replacing the label on the blood bag that had a wrong label applied?

 Revising process parameters in response to complaints?

 Revising equipment maintenance procedures to reduce drift in process specifications?

 Auditing all technicians of testing process after a quality issue with one technician had been indentified?

 Rewelding a contact that does not meet visual inspection requirements?

NON-CONFORMANCES ME-L12

Requirement, SOP, Specification

TYPES:

Deviations: e.g. volume in a tube Out of specifications: e.g fridge temperature: 15 °C (Specification: 4-8°C) Complaint: e.g Surgeon complaint that the tubing of the bag was leaky Audit finding: e.g training was not performed against SOP 151 Trending quality review: e.g trend analysis of product quality – leucocytes concentration Recall: e.g recipient with fever after transfusion of platelets -> recall of associated comonents : FFP and EC

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THE CAPA PROCESS ME-L12

PROCESS OUTPUT

• Identification & • Change control • Deviations Data Analysis • Dissemination of • OOS • Risk assessment information • Audit findings • Immediate action • Document • Complaints (correction) change • Trending • Root cause • Training Investigation • Recall • Action Plan CAPA NON- • Implementation CONFORMANCE & follow up

INPUT

1. IDENTIFICATION ME-L12

Non-conformance need to be clearly defined:

- Collect all available information -Usethe6W’s: What?, When?, Where?, Who?, Which?, Why? - Summarise in a detailed and concise description

 A well documented non-conformance is a non- conformance which can be solved

Example: : The stability of product XWY failed : The assay result of the 24 months stability testing of batch 126543 of product XWY is Out of Specification. Specification: 95.0 % -105.0%, Result: 93.4%

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2. RISK ASSESSMENT ME-L12

Evaluation to determine the need for immediate, corrective and preventive actions and level of action required based on impact and risks:

-Potentialimpact;

- Risks to patients, related to the safety and quality of the product, staff, blood establishments;

- Risks to donors;

- Immediate action that might be required.

4. IMMEDIATE ACTION ME-L12

Immediate action is necessary, when the quality, efficacy or safety may be compromised

Example of immediate actions:

- Product Recall; - Blockage stock of a blood component due to bacterial contamination; - Interruption of the processing (i.e. until the problem is assessed and fixed).

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5. ROOT CAUSE INVESTIGATION ME-L12

Systematic approach to be applied to ensure no root cause is missed:

• Common sense; • Multi disciplinary teams; • Keep open mind for different opinions.

ISHIKAWA/5M’s:

Problem Statement + Policies Causes + Procedures + Plant + Budget/Cost + Measurement + Management

6. ACTION PLAN ME-L12

- Summary of root cause analysis;

- Document the quality decision: e.g. no impact of the deviation on the product quality – product can be released;

- Action plan:Alltasks assigned to correct the problem and prevent the reoccurence are identified - Assignements of responsibilities and due dates - Details about required action and expected outcome

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7. IMPLEMENTATION & FOLLOW-UP ME-L12

- Execution of action plan;

- Document the action taken;

- Appropriateness & effectiveness of action evaluated of responsibilities and due dates;

- Closure of CAPA after sucessfull implementation, approved by QM.

NC MANAGEMENT FLOWCHART ME-L12

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NC MANAGEMENT FLOWCHART ME-L12

SUMMARY/CONCLUSION ME-L12

 NC/CAPA management need to be clearly defined;  Implementation of Root Cause Analysis should eliminate recurrence of NC;  NC/CAPA management is part of continuous improvement of a QMS.

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CHANGE CONTROL

Everything is changing…. Why should we control it? Module EImprovement - : Lecture 13 Continuous

Trainer: M. v. Roosmalen Lecture 13 - Day 3

ME-L13

TEACHING AIM

 Understand the concept of change control;  Learn all relevant aspects to implement and/or improve your change control system;  Know the whole process from initiation to implementation;.

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WHY CHANGE CONTROL? ME-L13

• Guarantee that all changes are evaluated for their effect on product quality and validation status • To ensure that changes are introduced in a controlled and coordinated manner • To identify and reduce risks • Uncontrolled changes carry significant risks of loss of the validated status

ME-L13 DEFINITIONS

CHANGE CONTROL DEFINITION: « A formal system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect a validated status of facilities, systems, equipment or processes. The intent is to assess the impact and risks and to determine the need for action that would ensure and document that the system is maintained in a validated state» (CoE Guide) KEY WORDS: Formal system, qualified representatives, changes, affect validated status, impact & risks, actions, maintained.

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REGULATIONS ME-L16

Directive 2005/62/EC

No explicit requirement of a CC system

All procedures, premises and equipment that have an influence on the quality and safety of blood and blood components must be validated prior to introduction and be re-validated at regular intervals determined as a result of these activities

CoE Guide

All modifications, enhancements or additions to validated systems and equipment must be managed through the blood establishment's change control procedure. The effect of each change to the system or equipment, and its impact on quality and safety,mustbe determined in order to identify the extent of revalidation that is required.

REGULATIONS ME-L13

Good Practices Guidelines

1.2.12.

A formal change control system must be in place to plan, evaluate and document all changes that may affect the quality, traceability, availability or effect of components or safety of components, donors or patients.

The potential impact of the proposed change must be evaluated and the degree of revalidation or additional testing, qualification and validation needed must be determined.

4.5.

Change control procedure should ensure that sufficient data are generatedto demonstrate that revised process results in a product of the desired quality, consistent with the approved specifications; Written procedure should be in place to describe the actions taken when a change is proposed; Changes should be formally requested, documented and accepted; Impact should be evaluated, including a risk analysis; Need for re-qualification and re-validation should be determined; Some changes may require notification to, or license amendment from, a national regulatory authority.

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REGULATIONS ME-L13

EU GMP – Chapter 1 No explicit requirement of a CC system Significant changes to the [manufacturing] process have to be validated [chapter 1.2 (ii) Changes carried out to the processes or analytical methods have to be reviewed regularly [chapter 1.4 (v), on PQR] EU GMP – Annex 15 Written procedures [no. 43] All changes treated formally, impact to be evaluated, need of revalidation to be determined [no. 44] PICS/S for Blood establishments

A formal change control system should be in place to evaluate and document all changes that may effect the collection, preparation, storage, dispatch, quality control and quality assurance of blood and blood components.

The potential impact of the proposed change on the quality of the blood component should be evaluated.

Scientific judgement should determine what additional testing and validation studies are needed to justify a change in a validated process.

ME-L13 CHANGES WILL HAPPEN

- Proactively due to business or technical reasons (e.g. new supplier, new equipment…) - Reactively driven as part of CAPA (e.g. due to deviations, OOS, trend analysis, audit observations)

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ME-L13 EXAMPLES REQUIRING CC

- New products, processes, critical materials, software, hardware, buildings, installations, specifications - Process changes (process times, storage times, storage temperatures, test methods, software) - Changes of critical materials, or supplier - Changes of critical equipment or parts or supplier - Changes regarding (collection) facilities (move, reconstruction)

WHAT SHOULD YOU THINK ME-L13 ABOUT?

- What do you want to change and why - Who is involved? - What are the consequences? - What are the risks? - What can you do to reduce or to eliminate the risks? - When are you going to do what (planning, time-schedule)?

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CHANGE CONTROL PROCESS ME-L13