Quality Management and Accreditation in Hematopoietic Stem Cell Transplantation and Cellular Therapy: The JACIE Guide

> Mahmoud Aljurf John A. Snowden Patrick Hayden Kim H. Orchard Eoin McGrath *Editors*

Quality Management and Accreditation in Hematopoietic Stem Cell Transplantation and Cellular Therapy

Mahmoud Aljurf • John A. Snowden Patrick Hayden • Kim H. Orchard Eoin McGrath Editors

# Quality Management and Accreditation in Hematopoietic Stem Cell Transplantation and Cellular Therapy

The JACIE Guide

*Editors* Mahmoud Aljurf King Faisal Specialist Hospital and Research Centre Riyadh, Saudi Arabia

Patrick Hayden St. James's Hospital Dublin, Ireland

Eoin McGrath JACIE Accreditation Offce EBMT Barcelona, Spain

John A. Snowden Department of Haematology University of Sheffeld Sheffeld, UK

Kim H. Orchard University Hospital Southampton NHS FT and University of Southampton Southampton, UK

This book is an open access publication. ISBN 978-3-030-64491-8 ISBN 978-3-030-64492-5 (eBook) https://doi.org/10.1007/978-3-030-64492-5

© The Editor(s) (if applicable) and The Author(s) 2021

**Open Access** This book is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this book are included in the book's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the book's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specifc statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use.

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# **Introduction**

For over 20 years, transplant professionals all over the world have been working with the FACT-JACIE Standards for haematopoietic stem cellular (HSC) therapy as a means to improve the care and services provided to their patients and donors and as a framework within which to pursue continuous improvement. The FACT1 and JACIE2 accreditation schemes stand out for the high take-up among centres not only in high-income countries but also the increasing interest in quality among transplant professionals in low- to medium-income countries.3 This success is testimony to the efforts of the community as a whole.

The ongoing evolution of the standards over the years demands that quality management systems can adapt to new needs and requirements, not just for accreditation but also to meet changing regulations and best practice. This handbook aims to be a professional resource on how to approach those challenges faced by many transplant programmes worldwide. The intended readers are not only centres at the beginning of their quality journey but also those centres with the experience of several accreditation cycles but with staff assuming new responsibilities for quality management.

The chapters offer different perspectives on approaches to common challenges and the reader is invited to refect on how to best incorporate and adapt them to the realities of their own institutions. The topics include, among others, good documentation practice, internal audits, validation and qualifcation, outcome analysis, personnel requirements, performance measurement, tracking and traceability, adverse events and CAPAs, maintaining the quality of management programme and risk management.

The authors are all professionals working in quality in cellular therapy with a combined wealth of practical experience.

<sup>1</sup>www.factwebsite.org

<sup>2</sup>www.ebmt.org/jacie-accreditation

<sup>3</sup> datahelpdesk.worldbank.org/knowledgebase/articles/906519-world-bank-country-and-lending-groups

In the future, JACIE, as part of the EBMT, an international collaborative peer network of professionals working in centres and as individuals in the feld of clinical bone marrow transplantation and cellular therapy, intends to issue revisions of this guide and to also assess how to exploit the contents as material for ongoing training and education as part of the EBMT's wider education strategy.

JACIE (Joint Accreditation Committee – ISCT & EBMT) is the EBMT committee established for the purposes of assessment and accreditation in the feld of haematopoietic stem cell transplantation (HSCT). The Committee was founded in 1998 by the then-European Group for Blood and Marrow Transplantation (EBMT) and European members of the International Society for Cellular Therapy (ISCT). JACIE largely modelled itself on the US-based Foundation for the Accreditation of Cellular Therapy (FACT), established in 1996 by the ISCT and the American Society for Blood and Marrow Transplantation (ASBMT). JACIE continues to actively collaborate with FACT on maintaining standards for the provision of quality medical and laboratory practice in HSCT, and the two organisations jointly publish the FACT-JACIE international standards.

The Co-editors


# **Contents**




# **Contributors**

**Mahmoud Aljurf** Oncology Center, King Faisal Specialist Hospital & Research Centre, Riyadh, Kingdom of Saudi Arabia

**Amal Alseraihy** Department of Pediatric Hematology Oncology, King Faisal Specialist Hospital & Research Centre, Riyadh, Kingdom of Saudi Arabia

**Judit Amposta** Freelance Quality Consultant, Mataró, Barcelona, Spain

**Julie Dolva** Hematology Department, Oslo University Hospital, Oslo, Norway

**Riad El Fakih** Oncology Center, King Faisal Specialist Hospital & Research Centre, Riyadh, Kingdom of Saudi Arabia

**Anne Emmett** BMT, Blood, Cells and Cancer, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK

**Fazal Hussain** College of Medicine, Alfaisal University, Riyadh, Saudi Arabia

**Phuong Huynh** Hematology Service, Institut Jules Bordet, Brussels, Belgium SPF Securité sociale DG-HAN, Brussels, Belgium

**Dunia Jawdat** Cord Blood Bank, Saudi Stem Cell Donor Registry, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia

Department of Science, College of Science and Health Professions, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia

**Dieter Klarmann** Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Frankfurt, Goethe-Universität, Frankfurt am Main, Germany

**Ilknur Kozanoglu** Department of Physiology, Baskent University Medical Faculty, Ankara, Turkey

Adana Adult Bone Marrow Transplantation Centre, University of Baskent, Adana, Turkey

**Mara Magri** Hematology & BM Transplant Unit, ASST Papa Giovanni XXIII, Bergamo, Italy

**Raquel Espada Martín** JACIE Accreditation Offce, EBMT, Barcelona, Spain

**Eoin McGrath** JACIE Accreditation Offce, EBMT, Barcelona, Spain

**Renza Monteleone** Transfusion Service-Stem Cell Transplant Program, Grande Ospedale Metropolitano "Bianchi Melacrino Morelli", Reggio Calabria, Italy

**Waleed Rasheed** Oncology Center, King Faisal Specialist Hospital & Research Centre, Riyadh, Kingdom of Saudi Arabia

**Songul Tepebasi** Department of Quality Management, Adana Adult Bone Marrow Transplantation Centre, Adana, Turkey

**Lex Van der Gouw** Cell Therapy Facility (CTF), University Medical Center Utrecht, Utrecht, The Netherlands

**Nick van Sinderen** Cellular Therapy, Antoni van Leeuwenhoek, National Cancer Institute, Amsterdam, The Netherlands

**Olga López-Villar** Hematology and Hemotherapy Department, University Hospital of Salamanca, Salamanca, Spain

**Joaquim Vives** Servei de Teràpia Cel·lular, Banc de Sang i Teixits, Edifci Dr. Frederic Duran i Jordà, Barcelona, Spain

Musculoskeletal Tissue Engineering Group, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain

Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain

# **Chapter 1 Quality and Standards for Haematopoietic Stem Cells Transplantation Programs**

**Eoin McGrath and Dunia Jawdat**

# **Quality**

The word "quality" emerged in the fourteenth century from the Latin "qualis" and the French "qualitie" [1]. Quality in healthcare as we know it today can trace its origins back to the early twentieth century when a number of measures were taken to address great variations in medical education and care [2]. The WHO defnes quality of health care as "the extent to which health care services provided to individuals and patient populations improve desired health outcomes".1

Quality itself is not a static concept – in its dynamic form, it becomes continuous improvement [3]. Furthermore, quality *assurance* (QA), concerned with compliance, should not be considered to be the same as quality *improvement* (QI), which is defned as the framework we use to systematically improve the ways care is delivered to patients [4]. Quality improvement has been further defned as "the combined and unceasing efforts of everyone – healthcare professionals, patients and their families, researchers, payers, planners and educators – to make the changes

1www.who.int/maternal\_child\_adolescent/topics/quality-of-care/defnition/en/ consulted 11/06/2020.

E. McGrath (\*)

JACIE Accreditation Offce, EBMT, Barcelona, Spain e-mail: eoin.mcgrath@ebmt.org

D. Jawdat

Department of Science, College of Science and Health Professions, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia e-mail: jawdatd@ngha.med.sa

Cord Blood Bank, Saudi Stem Cell Donor Registry, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia

that will lead to better patient outcomes (health), better system performance (care) and better professional development" [5].

In 1966, Avedis Donabedian (1919–2000), one of the great pioneers of quality in healthcare, introduced the concepts of structure, process, and outcome as the basis to *evaluate* the quality of health care. "Structure" includes the settings, qualifcations of providers and administrative systems through which care takes place; "process" as the components of care delivered and "outcome" as recovery, restoration of function and survival [6]. These concepts will probably be familiar to readers today even if they are not aware of their origins. In HSCT, structure would include the physical facilities where care is delivered, the experience and qualifcation of the medical and laboratory teams, the overall support structure and regulatory and reimbursement frameworks. Process would be how the patient and the healthcare system interact, e.g. referral from primary healthcare provider to tertiary care and necessary testing. Outcome includes the effect of care on diseases and their prevention, such as the mortality rate, the error rate and the quality of life [7].

The concept of quality management (QM) has been known since the 1950s and applied by different sectors for many years. However, in the feld of cellular therapy, it is relatively new in comparison to quality assurance and quality control. The implementation of a QM programme with its components including quality control, quality assurance, quality assessment and quality improvement advances the quality of service provided for patients and helps programs and stem cell banks to address external threats and internal weaknesses which could negatively impact services and products.

In HSCT, different stakeholders have been identifed as holding an interest in ensuring that patients receive quality care: patients, referring physicians, payers, other community healthcare providers, and professional and patient organizations [8].

#### **Standards**

A standard has been defned as "a desired and achievable level of performance against which actual performance is measured" [9]. Standard-setting organisations also consider themselves as facilitators of the above-mentioned evolution from compliance towards improvement [10].

In 1998, the European Society for Blood and Marrow Transplantation (EBMT) and the International Society for Cellular Therapy (ISCT) established the Joint Accreditation Committee – ISCT & EBMT (JACIE) – to develop international standards and offer an inspection-based accreditation process in the feld of HSCT. JACIE is a committee of the EBMT, and its members are appointed by and are accountable to the EBMT Board and ISCT is represented through two members of the Committee. JACIE collaborates with the US-based Foundation for the Accreditation of Cellular Therapy (FACT), a non-proft corporation co-founded by ISCT and the American Society of Transplantation and Cellular Therapy (ASTCT), which pioneered the standards and accreditation model starting in the mid-1990s in the USA. JACIE and FACT develop and maintain global standards for the provision of quality medical and laboratory practice in cellular therapy. The FACT-JACIE international standards stand out as an example of a profession-driven initiative to improve quality in transplantation which have subsequently been incorporated by third parties to support healthcare reimbursement (health insurers, social security) and authorization of treatment (regulatory authorities) processes.2

In 1974, the frst bone marrow registry was founded in the UK, and since then many registries have been established around the world. Hence, for more than four decades, bone marrow registries have been crucial in facilitating the search for haematopoietic stem cells from adult donors or cord blood units for any patient around the world.

In 1988, three pioneers in the feld of blood stem cell transplantation, John Goldman, E. Donnell Thomas and Jon J. van Rood, initiated the founding of the Cooperative Marrow Donor Programme, an international collaboration that was essential at that time and led to the offcial founding of the World Marrow Donor Association (WMDA) in 1994 in Leiden in the Netherlands to give all patients equal access to high-quality stem cells for clinical transplantation by providing international standards and guidelines relating to best practices in every aspect of the registry's operation promoting quality and donor safety. The WMDA established an accreditation programme for unrelated donor registries as an assurance to all organizations involved in HSCT.

Together with FACT accreditation of stand-alone cord blood banks, WMDA accreditation reassures transplant physicians in terms of the quality of product and services provided.

In 2007, EBMT, the Center for International Blood & Marrow Transplant Research (CIBMTR) and the Asian Pacifc Blood and Marrow Transplantation Group (APBMT) together with WMDA among others founded the Worldwide Network for Blood and Marrow Transplantation (WBMT), a non-proft scientifc organization aiming to promote excellence in stem cell transplantation, donation and cellular therapy.

Standards in cell therapy are offered through what are typically voluntary schemes such as AABB,3 JACIE,4 FACT,5 NetCord6 and Fundación CAT7 among others and serve to promote patient care and excellence in clinical and laboratory practice by standardizing procedures for the collection, analysis, banking

<sup>2</sup> https://www.ebmt.org/regulations-guidelines consulted 22/07/2020.

<sup>3</sup>www.aabb.org/sa/standards/ consulted 11/06/2020.

<sup>4</sup>www.ebmt.org/jacie consulted 11/06/2020.

<sup>5</sup>www.factwebsite.org/ consulted 11/06/2020.

<sup>6</sup>wmda.info/professionals/quality-and-accreditation/netcord-fact-standards/ consulted 11/06/2020.

<sup>7</sup>www.catransfusion.es/.

and administration of cells for transplantation [11]. As an example, the JACIE and FACT accreditation systems are based on the regular update of standards covering the entire transplantation process, from the selection of the donor/ patient to the follow-up, including collection, characterization, processing and storage of the graft. Considering the different competences included in the process, the standards are articulated in 4 parts: Clinical Programme, Bone Marrow Collection, Apheresis Collection and Processing Facility. A QM section is embedded in each part, aimed to provide a tool for both the applicants to develop a comprehensive quality system and the inspectors to check the compliance of the transplant programme to the standards. Processing labs can apply independently; however, the target of the accreditation is the programme, intended as the process in its entirety, thus requiring a full integration of units, laboratories, services and professionals. Each section focuses on the competence of personnel, listing the topics for which the evidence of specifc training is required and also including the minimum requirements of experience for positions of responsibility. Maintenance of competencies is also required for all professionals.

The standards are revised on a 3-yearly basis by a commission formed by experts appointed by FACT and JACIE, including specialists in HSCT administration, cell processing and storage, blood apheresis, transplant registries and QM. The standards are based on published evidence and, when this is not available, on expert consensus. A legal review and comparison with current regulations is carried out for each version. When the developmental phase is fnalized, the standards are published for public review and comment before being approved by FACT and JACIE. The standards incorporate sound principles of quality medical and laboratory practice in cellular therapy, but they do not cover the legal requirements which fall to the relevant competent authorities.

The standards cover the use of different sources of hematopoietic stem cells and nucleated cells from any hematopoietic tissue source administered in the context of the transplant process, such as donor lymphocyte infusion (DLI). The inclusion of the term "hematopoietic" in the title is to defne the scope of these standards due to an increasing number of accredited facilities that also support non-hematopoietic cellular therapies. Since the release of edition 6.1 in 2018, the standards have included new items specifcally developed for other cellular therapy products, with special reference to immune effector cells (IEC). This refects the rapidly evolving feld of cellular therapy through mainly, but not exclusively, genetically modifed cells such as CAR-T cells. The standards do not cover manufacturing of such cells but include the chain of responsibilities where the product is provided by a third party, usually a pharmaceutical manufacturer, and ensure the competence of the personnel in the management of adverse events related to the infusion and subsequent care.

#### **Impact**

What if any is the impact on clinical outcomes? – a crucial question given the effort and resources needed to establish and maintain the required standards in each transplant centre and subject to much investigation across healthcare at large [12]. Evidence does exist for HSCT where studies using European HSCT registry data have correlated the different phases of preparation for and achievement of accreditation at centre level with incremental improvements in patient survival and reduction in procedural mortality [13, 14]. Evidence relating clinical trials participation and FACT accreditation in the United States also indicated a positive impact, although with some mixed fndings [15].

Implementing a quality management system and achieving accreditation in the feld of cellular therapy by a transplant centre prove the level of commitment to high-quality measures and monitoring cellular therapy practice and downstream patient care. This provides reassurance to patients and their families, healthcare professionals, commercial suppliers, regulatory authorities and insurance payers.

Standards-setting organizations must be alert to the risk of overburdening their users with requirements, falling behind the pace of change or losing the focus on what actually matters to patients: health, safety and optimal experience [12, 16]. Braithwaite *et al* propose the need for a new generation of standards that do not just assess compliance but also enable healthcare system transformation and sustainability [16].

#### **Conclusion**

The international take-up of specialized standards in a complex feld such as HSCT is due to a number of factors: the early championing by some HSCT leaders emphasizing the need for quality measures to better control a complex process; international professional association support; the early observation at local level of the organisational impact and inclusion among national regulatory requirements. This widespread acceptance then provides a basis to present other aspects, such as standardised performance benchmarking of survival outcomes and minimal centre activity, as further means of quality improvement.

To help guard against overburdening users with unwieldy requirements, ultimately, we must keep in mind why quality – and by extension, standards – is important. Avedis Donabadian said in an interview not long before he died: "Ultimately the secret of quality is love. You have to love your patient, you have to love your profession, you have to love your God. If you have love, you can then work backward to monitor and improve the system" [17]. This simple but powerful statement captures the real purpose of quality.

#### **Key Points**


## **References**


plantation. J Clin Oncol [Internet]. 2011; 29(15):JCO.2010.30.4121-. Available from: http:// jco.ascopubs.org/cgi/content/abstract/JCO.2010.30.4121v1.


**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

# **Chapter 2 Development of Organizational Quality Management System**

**Phuong Huynh and Renza Monteleone**

FACT-JACIE accreditation is how a HSCT programme can demonstrate that it is performing to a required level of practice in accordance with agreed quality standards in haematopoietic cell therapy (HSCT). An essential component of accreditation is that a centre must demonstrate that it operates an effective quality management system (QMS). Development of a comprehensive quality management system is often the most challenging and time-consuming exercise that the transplant programme encounters when preparing for accreditation (Chap. 14).

The FACT-JACIE Standards defne a quality management system as 'an organization's comprehensive system of quality assessment, assurance, control, and improvement'. A quality management system is designed to prevent, detect and correct defciencies that may adversely affect the quality of the cellular therapy product or increase the risk of communicable disease introduction or transmission. It may also be referred to by other terms [1].

A quality management system (QMS) is a mechanism to ensure that procedures are being carried out in line with agreed standards with full participation by all staff members. In a cell transplant programme, this ensures that the clinical, collection and laboratory units are all working together to achieve excellent communication, effective common work practices and increased guarantees for patients. It is a means of rapidly identifying errors or accidents and resolving them so that the possibility of repetition is minimised. It assists in training and clearly identifes the roles and responsibilities of all staff. Once the required level of quality has been achieved, the

P. Huynh (\*)

SPF Securité sociale DG-HAN, Brussels, Belgium

R. Monteleone

© The Author(s) 2021 9

Hematology Service, Institut Jules Bordet, Brussels, Belgium

Transfusion Service-Stem Cell Transplant Program, Grande Ospedale Metropolitano "Bianchi Melacrino Morelli", Reggio Calabria, Italy

M. Aljurf et al. (eds.), *Quality Management and Accreditation in Hematopoietic Stem Cell Transplantation and Cellular Therapy*, https://doi.org/10.1007/978-3-030-64492-5\_2

remaining challenge is to maintain this standard of practice. With a working quality management system in place and adequate resources, the fundamental elements necessary to sustain the program are continued staff commitment and vigilance.1

The QMS in the FACT-JACIE standards establishes a framework for everyday delivery of HSCT (clinical, collection, processing) in the centre. It also includes guidelines for purchasing, human resources and document control related to the cellular therapy product and patient and donor management. In addition, the QMS includes the preparation of the quality management plan (QMP, or quality manual) (see also Chap. 13), writing of the SOPs, describing necessary processes and their interactions, and the preparation of templates for different kinds of documents and records that will be used (see Chap. 3). These are subjected to very careful scrutiny by management reviews (see Chaps. 6, 9, and 12), internal audits (see Chap. 4) and Corrective and Preventive Actions (CAPA) procedures to deal with and correct any non-conformities detected to keep the quality management system effective (see Chap. 11).


<sup>1</sup>www.ebmt.org/accreditation-defnitions

	- All centres' staff should have clearly defned roles and responsibilities and these should be shown on the organisational chart (Table 2.1). This could then be further explained in the QMP, especially the responsibilities, the Job Descriptions or the contact information. If staff are not directly employed by the same institution, honorary contracts may be necessary. An honorary con-

**Table 2.1** List of the personnel who work within the transplant programme at the centre who could appear in the organigramme


tract gives individuals the right to work in more than their own institution and is good evidence of integration across different organisations.

– The FACT-JACIE standards require that the QMS includes an organigramme or organisational chart (see Chap. 7), i.e. visual representation of the structure of all parts of the HSCT programme, and makes clear who is responsible for what aspects of which services (collection/clinical/processing). It should illustrate who reports to whom and who has responsibility for the different aspects of the transplant programme (Figs. 2.1, 2.2 and 2.3). The structure will enable both new/existing staff and external organisations to easily identify the make-up of the programme and lines of authority. Patients could also be provided with information about the team who are looking after them. The HSCT programme will need to show where the collection and processing take place and the individuals involved. Third-party collection and processing services are likely to have their own QMS which is perfectly acceptable if there are service-level agreements (SLAs, Chap. 8) or contracts in place that defne how the respective QMS interact.

Below is a list of roles that should be considered for inclusion in the programme organigramme and sample organisational charts showing differently structured programmes.

The Quality Assurance and Performance Improvement System is a coordinated, comprehensive and systematic plan for monitoring and continuously working to improve the services to support the care that patients receive. It will assist staff in

**Fig. 2.1** Example 1 of organisation chart template

**Fig. 2.2** Example 2 of organisation chart template

**Fig. 2.3** Example 3 of organisation chart template

meeting their individualized objectives and shall be managed by the quality manager. Quality managers are responsible for the development, implementation and maintenance of the QMS, while the clinical program directors, in collaboration with the respective collection and processing directors, shall retain overall responsibility for quality.

Depending on how the HSCT programme is organised and its size, there may be a single quality manager or separate quality managers for each service, i.e. clinical, collection and processing.

Although the overall responsibility for the quality of the HSCT programme lies with the services directors, the quality manager has key roles including, but not limited to, the following:


The quality manager must understand how the HSCT process works in various settings (allogeneic, autologous, etc.) and the steps patients and donors follow, for example:


The quality manager must also use standardised control documents, meetings with staff from each of the services, audits as well as methods for reporting, investigating and correcting adverse events whether the HSCT service is fully integrated or comprised of three separate facilities.

One of the key aims of the QMS should be to improve communication and understanding of roles and responsibilities across all the different staff groups within the HSCT program. Poor communication between groups of staff is cited as one of the biggest single causes of quality programme failure [3]. Joint Commission sentinel events analysis between 2004 and 2014 consistently showed poor communication as a contributor to failures or ineffciencies of processes [4].

A quality programme will only be successful if there is communication between all the staff involved. Regular group and team meetings should be set up to maintain and increase integration and ensure that different systems work together (Table 2.2). The QMS and QMP are central to improving communication between staff and departments and to ensure that everybody is clear about roles, responsibilities and processes for decision-making. Examples of template agendas and signing in sheets


**Table 2.2** Suggested quality groups/teams

serve as evidence of meetings, joint decision-making and integration within the HSCT programme.

Below are suggestions of the types of groups that should be contributing to the maintenance of the QMS [5].

#### **References**


**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

# **Chapter 3 Document Development, Implementation, Review, Archive, and Disposal**

**Nick van Sinderen**

## **General**

Documents have many uses in the quality management program. They provide the structure needed for quality assurance through policies and procedures, ensure quality control through forms such as pre-printed orders and worksheets, and support quality management activities through audit reports, outcome analyses, and training records. The quality program needs to identify documents critical to the transplant program. The transplant program needs to describe how the critical documents are conceived, generated, implemented, distributed, reviewed, and stored. All parts of the transplant program require written instructions as to how to undertake key processes. Equally, personnel in the facility should use these documents to carry out tasks and they need to be sure that the document they are using is the current version. Documents (policies, Standard Operating Procedures (SOPs), worksheets, and forms) are the foundation of the quality program as they explain how tasks are undertaken and facilitate the effective operation of the transplant service. An overarching policy encompassing the writing, reviewing, implementation, and control of documentation (the "SOP about SOPs") is a key requirement.

N. van Sinderen (\*) Cellular Therapy, Antoni van Leeuwenhoek, National Cancer Institute, Amsterdam, The Netherlands e-mail: n.v.sinderen@nki.nl

© The Author(s) 2021 17 M. Aljurf et al. (eds.), *Quality Management and Accreditation in Hematopoietic Stem Cell Transplantation and Cellular Therapy*, https://doi.org/10.1007/978-3-030-64492-5\_3

#### **Start**

Setting up a document management system (DMS) starts with making an inventory of what you have and of what you need. What do you think is required and what are the JACIE requirements? The standards provide a structure whether you are starting from square one or whether you already have a set of transplant-related policies. Transplant centers frequently have pre-existing laboratory and, less commonly, clinical policies, though, very often, the system is so fragmented that many staff are unaware of their existence. From the outset, it is imperative to form a project team as the task is huge and needs constant monitoring and steering.

Some key points to consider:

– Use your in-house expertise

If you make your expertise the starting point, you will make the DMS your own. In the development of documents, review the draft contents against the JACIE requirements. This will lead to useful discussions which will increase the value of your SOPs.


Use the quality manual as your starting point. This is a high-level document, so avoid excessive detail and try to keep it short. Refer to SOPs and other relevant documents. In your SOPs, refer to checklists and additional information elsewhere *(see Fig. 3.1).* This makes them more readable and accessible.

Example set-up of the quality manual


**Fig. 3.1** Example document structure


#### **Workfow**

The quality manager has overview of all documents and is usually assisted by document managers who are clinicians or scientists with a part-time role in quality (see Fig. 3.2). This is a constructive approach in that such individuals have areas of expertise which relate to the documents assigned to them. They are therefore best positioned to ensure that the relevant policies are ft-for-purpose.

The quality manager is the direct link to transplant program management and is responsible for the implementation of the QMS. The quality manager provides a quarterly report to the clinical program director and the management team to keep them up-to-date regarding new documents and revised versions of existing documents. These quarterly reports are included in the annual report and the annual management review, completing the policy Plan-Do-Check-Act (PDCA) cycle for this topic.

#### **Quality Manager**


**Fig. 3.2** Create and review documents

– Author

The frst author of a document leads in its preparation and writing and should have relevant expertise. The goal is to produce an advanced draft ready for wider review. This provides an educational opportunity which will be addressed further later in this chapter.

– Reviewer(s)

These are one or more individuals who check the document for factual accuracy and clinical relevance. If required, suggested improvements can be incorporated into a revised version. This person is often from another department and provides different expertise. Such a fresh perspective is often very useful. An example would be a pharmacist reviewing medical policies from the point of view of pharmacovigilance. This is a common approach and helpfully ensures that pharmacists are aware of all new treatments.

– Authorization

The clinical program director (CPD) is ultimately responsible for the transplant program and the CPD (or his/her designee) therefore authorizes all documents. However, the CPD does not necessarily need to review and authorize each document. That would take an additional work week. The non-medical documents can be delegated to members of the management team or the relevant senior, qualifed individuals. In such cases, this should be carefully documented in the DMS SOP. If necessary, the CPD can review document metadata in order to monitor its development. These changes can be summarized in the quarterly and annual reports.

Note: Electronic document management systems generally allow for each step in the process to be tracked. This is not the case with paper-based or hybrid systems and care is needed in such cases to ensure that the workfow is robust and easy to operate.

#### **Responsibilities**

Involve as many staff as possible when developing new documents. This is crucial. It is common at inspections to fnd that the DMS has deteriorated – missed review dates, obsolete policies – as too few people have too many documents to take care of. Tasks end up being repeatedly deferred. This can be dangerous for both patients and clinical staff as treatment protocols must be kept current and have the latest information. It is the job of the quality manager to ensure that newly authorized documents are immediately made available for routine use.

Here are some examples of the appropriate staff to be involved in developing particular policies:


Medical systems differ and you will need to adopt an approach that best suits your local circumstances. However, the key take-home message is to involve as many people as possible in order to keep the system going in the long term.

# **Duplication of Requirements Between Different Quality Systems**

Anyone involved in quality is aware of the overlapping requirements between quality systems such as JCI, JACIE, and ISO. The transplant unit may be a component of a wider oncology program; a pharmacy-based QMS might be subject to a different regulator; the pediatric unit may be administratively distinct from the adult unit; and there are often a number of different information and communication (ICT) services networks – whether national, regional, or hospital-based – all available on local workstations. Equally, the hematology laboratory may be accredited to ISO 15189:2012 (medical laboratories – requirements for quality and competence). In general, there are few signifcant differences between these standards. A useful approach is to follow the stricter guideline and to try to avoid following separate regulations in a given area as it may lead to confusion. For example, if JCI requires three-yearly review and JACIE two-yearly, follow the JACIE requirement.

Unfortunately, the different international standards have evolved and diverged over time, and it is important to bear in mind when creating DMS policies that they meet all of the different regulatory requirements. Inspectors and the EBMT can be made aware of these issues.

Each transplant unit has unique circumstances, based on local logistics and resources. So it is not possible to be prescriptive. Rather, the key principles to remember are that documents need to be kept up-to-date and accessible for everyone involved. Important underlying concepts include the use of technical solutions, cross-referencing between documents to prevent redundancy, and close collaboration with other hospital departments, especially ICT, when setting up and also on an ongoing basis to maintain the DMS.

#### **ICT Systems and Paper Documents**

Recent ICT advances have included hospital-wide electronic patient records (EHRs) and remotely accessible document management systems. Some of these allow for treatment protocols to be automatically included in patient records, guaranteeing the use of the current version. More usually, however, each transplant unit is a patchwork of promising innovations and local logistical limitations. The challenge might be physical due to lack of space or fnancial due to inadequate investment. Some departments manage to set up their own bespoke IT systems. Although an attractive short-term solution, this can pose problems. The hospital ICT department will not provide support when something goes wrong and such a system can leave the unit dangerously reliant on one motivated individual.

A paper-based DMS offers a reasonable alternative but has some challenges of which you need to be aware. These include the revising of policies, fling and archiving, and how to keep everyone informed of new versions of documents. This is the system where you see frequent handwritten notes. If following Good Documentation Practice guidelines, every written update to a document must be signed and dated. This is not likely to happen in a hectic hematology department.

Here again, there is no one-size-fts-all solution. However, using a collaborative common sense approach, it should be possible to put in place a workable system that meets the standards. The basic question you always have to ask yourself is, "How do I get the latest version of the document to the people that use it?"

#### **Education and Document Management**

A document management system is a perfect tool for education. Here are some examples:


These are just a few examples of how you can use document management systems for educational purposes. Refect on how this can be done to beneft your program.

#### **JACIE on Document Management**

The document control policy shall address the points listed in Fig. 3.3

The JACIE document management standards are straightforward. Documents should have a standard format and should be revised every two years with clear revision dates and tracked changes. They must be authorized by the CPD or designee, contain accurate references, and information on "who modifed what, at what time, and why" should be clearly recorded. Methods to ensure safe validation of both electronic and printed versions are also required. Finally, and importantly, maintain a readily available list of all critical documents.

Documents may require revision for several reasons:


The DMS SOP should clearly describe these processes. Documents should be easily accessible. Finally, maintain open communication with all staff in the


**Fig. 3.3** JACIE and document management

transplant program and make sure management is aware of all signifcant developments.

Note: Refer to the JACIE/ EBMT manual for the standards and guidance in their implementation.

#### **Source for fgures**

1. Figures 1 and 2 were created by the author, and Figure 3 is from the EBMT Standards quality management presentation.

**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

# **Chapter 4 Audits**

**Olga López-Villar and Julie Dolva**

# **General Concepts**

## *Defnition and Purpose*

An audit can be defned as a documented, systematic evaluation to determine whether approved policies or standard operating procedures have been properly implemented and are being followed [1, 2].

Audits represent one of the principal activities of the quality management program. They are conducted to establish whether the program is operating effectively and to identify trends and recurring problems in all aspects of facility operations. Of course, an audit can also demonstrate strengths.

A common mistake is to see the audit, particularly external audits, as the goal of the quality system. The idea – "I have just passed the JACIE audit so I can relax until the next one" – is a misunderstanding of what audits are for.

## *Scope*

The scope of the audit can range from simple to complete. It can examine a particular process, the quality system itself (quality audits), or the whole program.

O. López-Villar (\*)

Department of Hematology and Hemotherapy, University Hospital of Salamanca, Salamanca, Spain e-mail: olgalopez@usal.es

J. Dolva Hematology Department, Oslo University Hospital, Oslo, Norway e-mail: jdolva@ous-hf.no

The scope must be described in detail in the audit plan. Audits and the audit plan are part of the quality management system. Depending on the organization of internal audits in a center, the unit can be audited within a single (and comprehensive) internal audit or there can be different audits for different topics.

#### *Types of Audits*

Internal, third party, and external audits [3]:


Another example is that of units being audited by manufacturers of CAR-T cells. In this case, the unit (clinical, collection, or processing) does not perform the audit; it is analyzed by the company's auditor.

	- Performed by external certifcation or accreditation body: JACIE, ISO9001, etc.
	- Inspections by the competent authority

These certifcation or accreditation entities require internal audits to assess the system.

It would be unnecessarily time-consuming if units had to arrange dedicated internal audits to meet the specifc requirements of each accreditation body. It is therefore advisable to make sure to include all requirements in the audit procedure.

Deviations detected in third-party and external audits should be managed according to the center's corrective action and preventive action (CAPA) policies in the same manner as those detected in internal audits.

Other ways of classifying audits are as follows:

• On-site vs document:

*On-site* The auditor visits the unit to perform the audit (on-site). The auditor may examine documents relating to the scope of the audit or procedures performed on the day of the audit, interview personnel, etc.

*Document* Alternatively, the audit can consist of a review of documents submitted by the center. This type of audit is not generally recommended for internal audits and is best reserved for interim audits or for audits of remote third-party providers.

• Audit for accreditation or re-accreditation vs interim audit: more details in Chap. 14 (the accreditation process).

The audits for accreditation or re-accreditation are the ones performed to check the system and obtain the accreditation.

The interim audit is performed during the accreditation cycle to assess that the quality management system is still functioning according to the standards.

This chapter is dedicated to internal audits.

#### **Auditor Requirements**

An auditor requires suffcient expertise in the subject manner to be able to identify problems and must also be a competent auditor.

Knowledge of the subject being audited is often needed to perform internal audits. The organization must be able to demonstrate how they assess auditor competency. Examples could include courses, audits performed, etc.

The auditor can be a transplant program or unit staff member as long as they are not solely responsible for the process being audited and did not perform the audited activities [2].

#### **How to Perform Internal Audit: The Steps of an Internal Audit**

The program must have a description of precisely how they perform audits, specifying for the particular unit or program all the steps that are summarized in this chapter.

#### *Audit Calendar*

There must be a calendar or schedule of audits (Table 4.1). The auditor can be included in this calendar or in another of the documents. The head of the QM program should identify areas to be audited and audit frequency [2]. The calendar should be shared with key personnel at quality meetings. Depending on the structure of the transplant program, there may be one overarching program audit schedule or each unit may develop their own calendar.

Examples of audits can include the following:


There are mandatory audits required by JACIE or the institution, while other audits may be based on local requirements or problems and may be identifed by risk assessment, for example. There must be regular auditing of critical activities; the frequency will depend on the importance of these activities, and, to some extent, on the results [2]. There is a list of the minimum requirements in the JACIE standards. Most of the topics require an annual audit. To make it simple, annual audit for all topics is a reasonable approach.

The list of audits might have to be modifed or extended during the year, for example, to include follow-up audits.

#### *Audit Plan*

Preparation and planning are important parts of a good audit and must be done thoroughly. An audit plan is prepared as a specifc guideline for the audit and is essential to allow the auditor to perform an effective and effcient audit.

Depending on center procedures, auditors can use either a pre-existing checklist or a specifc checklist prepared by them which includes all the items to be audited. The JACIE checklist, or parts of it, could serve this purpose, depending on the scope, and other topics can then be included depending on the unit and on the quality system in use in the unit.

The use of checklists to perform the audit is not mandatory; other tools are acceptable if they cover all the topics that are to be audited.

The plan should include the actual date, location, etc.

#### *Conducting the Audit*

Depending on the audit procedure, a formal introduction may not be necessary.

During the audit, the auditor will review the process, the procedures, forms, etc., according to the audit plan. The auditor will interview the personnel to assess if what they do is performed according to the written procedures of the unit and according to the standards [4]. During the audit, the auditor collects evidence to assess adherence to standards. For the report, it is important to write down any evidence of a deviation in a particular requirement.

#### *Closing*

Depending on the procedure, a formal closing meeting may not be required. However, it may be useful to discuss the audit fndings with the individual responsible for the procedure or their designee and with the quality manager.

**Table 4.1** Example of an audit calendar for the Clinical and Marrow Collection Facility

## *Audit Report*

The audit report is an important document and must be prepared by the auditor within a pre-defned timeframe.

The use of a template (example in Table 4.2) is recommended to ensure that all the necessary details are included. These should include the following: audit title, scope, auditor, date, location, plan, copy of the checklist or of the audit fndings, summary of deviations, and signatures.


**Table 4.2** Example template for an audit report form. Adapted from "A practical guide to implement quality management in a Stem Cell Transplantation Programme" [5]


**Table 4.2** (continued)

The audit report should be reviewed and approved by the appropriate personnel, such as the quality manager and the facility director. The approved audit report should be distributed to the manager of the audited area and should be shared with staff, when appropriate [2].

Internal audit reports are always reviewed in external audits (JACIE, ISO, etc.), so it is important to make sure that the necessary reports are available for the inspector.

#### *Actions*

Audits are performed to recognize problems, trends, and improvement opportunities [1], and any fndings should be followed by the necessary actions. The center must identify the underlying root cause of the deviation and implement corrective and preventive actions (CAPA) (see Chap. 11) or process improvements, as required [2], ideally as soon as possible, and certainly within the required timeframe.

The corrective and preventive actions should include a scheduled date for a follow-up audit to verify that effective corrective actions have been implemented [2].

The required actions must be documented according to local procedures. The fndings of the audit can be included within the established system for recording deviations, occurrences, etc. (see Chap. 11).

The center can also choose to document the actions in the audit report (Table 4.3). The effectiveness of the actions must be reviewed and documented and further audits might be necessary.

In subsequent audits, it is important to review stages in the process where deviations have previously been found to occur.

#### **Communication of the Result of Internal Audits**

The results of the audits, as a key component of the quality management system, must be shared at quality meetings and included in the annual report.

Audit results, corrective actions, and follow-up actions should be reported at least once a year. Review by the Program Director should be documented and there should be evidence that audit reports have been shared with the appropriate staff [2].


**Table 4.3** Example template for corrective action plans. This table can be added to the audit report (Table 4.2) if the center decides to include the actions in the audit report instead of including them in the deviation procedure

Adapted from "A practical guide to implement quality management in a Stem Cell Transplantation Programme" [5]


**Table 4.3** (continued)

## **References**


**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

# **Chapter 5 Qualifcation and Validation**

**Renza Monteleone and Dieter Klarmann**

*Qualifed equipment* and *validated processes* ensure satisfactory, safe, and reproducible outcomes and allow personnel to achieve, within the limits of the precision of the process, the same output when starting with the same input. Any change of equipment, utilities, or process should be formally documented and the impact on the validation status or control strategy assessed (change control [Fig. 5.1]).

A process is validated by establishing objective evidence that the process consistently produces an expected endpoint or result that meets predetermined acceptance criteria. Process validations can be performed prospectively or concurrently.

The transplant program or facility should have a specifc SOP or document (validation master plan – VMP) related to qualifcation and validation, detailing which validation studies are mandatory, how to perform them, and in what format. The design of the validation study should be adequate to determine if the process reproducibly achieves the purpose for which it is intended.

In this SOP/VMP, the following items should be addressed:


R. Monteleone

D. Klarmann (\*)

© The Author(s) 2021 35

Transfusion Service-Stem Cell Transplant Program, Grande Ospedale Metropolitano "Bianchi Melacrino Morelli", Reggio Calabria, Italy

Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Frankfurt, Goethe-Universität, Frankfurt am Main, Germany e-mail: dieter.klarmann@kgu.de

M. Aljurf et al. (eds.), *Quality Management and Accreditation in Hematopoietic Stem Cell Transplantation and Cellular Therapy*, https://doi.org/10.1007/978-3-030-64492-5\_5

**Fig. 5.1** Validation study including risk assessment and qualifcation


The responsibility for the validation SOP/VMP lies with the director of the transplant program. However, responsibility is shared with the quality manager, who has the key role of deciding on the methodological tools to be used for qualifcation and validation by the professionals involved in this process. The quality manager is responsible for organizing and monitoring training and ensuring the competencies of the personnel involved in the validation studies as well as organizing training on change control and risk management. Finally, the quality manager verifes the implementation of and compliance with the validation SOP/VMP.

The result of each validation study must be reviewed and approved by both the quality manager and the transplant program director or facility director (collection, processing, or clinical) and/or by the individuals deemed responsible according to national pharmaceutical law.

All transplant program personnel should be involved in the validation studies. This can be achieved by establishing a dedicated validation team with representatives from across the transplant program. Professionals involved in the qualifcation and validation steps should have specifc training in the relevant area and in the processes to be validated. They should collaborate with the quality manager and, if required, external experts; for example, when qualifying equipment, this may necessitate the involvement of the hospital maintenance offce and the manufacturer.

A risk assessment should be performed for each validation study to assess how critical the process is and to defne the level of risk.

Qualifcation of the facility, equipment and material, and verifcation of personnel training are included in the validation study (Fig. 5.1).

# **Validation Process** (Fig. 5.2)

**Identifcation of critical processes to be validated** JACIE defnes some minimal mandatory validations, though every transplant program should decide whether additional processes are critical to their activities and might therefore merit formal

**Fig. 5.2** Steps to carry out a validation study and responsibilities

validation. A process is considered critical if it impacts on the quality and/or safety of cellular products.

The minimal Validation studies required by the JACIE Standards are as follows:


**Risk assessment** Evaluation of the level of risk and activities that might mitigate this risk (see Chap. 18 on Risk Management).

**Validation plan** For each critical process requiring validation, the facility should produce a validation plan that includes the following:


**Qualifcation: facilities, material, equipment, personnel** Each component that could infuence the results of the process should be qualifed. Qualifcation of facilities, for example, is based on the verifcation of suitability of the rooms for the proposed activities, verifcation of environmental conditions, access for authorized staff, certifcation, etc. Qualifcation of materials is based on the verifcation of the manufacturer's certifcation, integrity of packaging, expiration date, etc.

Qualifcation stages for equipment, facilities, utilities, and systems according to [1] are listed in Fig. 5.3:


**Competencies** The competency of personnel to perform the activities related to the process undergoing validation should be verifed and, if insuffcient, specifc training should be arranged. The validation team should check that there are SOPs for all the processes involved in the validation study and, if unavailable, need to generate such policies; registration forms need to be available to ensure that every step of the process can be clearly traced.

**Fig. 5.3** Qualifcation stages for equipment, facilities, utilities, and systems

**Validation tests** Based on the validation plan, an adequate number of tests should be performed. The number of tests required to consider the process validated will vary, based on the frequency of the respective activity, level of risk, precision, range of acceptable or expected results, etc. The rationale and the established number of tests should be documented. The validation study should include the parameters to be verifed, the expected results, the criteria and acceptance range, and the method for verifcation (test, visual assessment, document-based, etc.)

**Validation review and approval** Following completion of the validation, all data analyzed, the output and results should be included in a fnal validation report; the quality manager and the transplant program director and/or facility director should review the report and confrm with their dated signature that the process is validated and that it may be used for clinical purposes.

**Periodic validation** The transplant program or facility shall decide on the length of the validation cycle. This decision should be based on various factors, including the level of risk, the internal control process, equipment wear, and other components. The basis for this decision shall be described and documented.

**Change control** If a signifcant change is introduced in the process, it should be revalidated. A change control analysis is required before starting the validation study to predict the possible impact of the change on the process (Fig. 5.4).

## **Example of Documents and Registration Forms for Validation**

## *Validation Master Plan (VMP)*

General SOP or other document that describes how to perform a validation study.

# *Validation Study*

A specifc SOP or document that describes how to perform validation of a specifc process. It contains the specifcations of the process (phases, components to be qualifed, expected output, prerequisites and performances, type and range of evidence required to confrm that the process is validated).


**Fig. 5.4** Change control fowchart


Computerized systems used in the manufacture of medicinal products should also be validated according to the requirements of EU-GMP Annex 11; these are not included in this chapter, for details see reference [2].

## **Glossary**


produce a medicinal product/cellular therapy product meeting its predetermined specifcations and quality attributes


#### **References**


**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

# **Chapter 6 Outcome Analysis**

**Anne Emmett**

## **What Is Outcome Analysis?**

Outcome analysis does not directly assess the quality of performance, it only allows for interpretation of the quality of the process and structure of care. A set of key performance indicators (KPIs) should be established to 'measure' against.

Outcome analysis can be a subjective process as good outcomes can come from poor care and poor outcomes can come from good care. There are many interplaying factors that need to be considered and a 'one-size-fts-all' approach cannot be established. It is important to ensure that the intended outcome is consistent with the systems and processes put in place by each facility.

Ensure that the intended outcome measure is clearly defned and quantifable. Ways of measurement can be against a scale, by questionnaires, direct observation, or retrospective review of data.

Policies and procedures should describe in detail the steps to be taken to perform outcome analysis. The process for outcome analysis should follow the PDCA quality cycle processes of Planning (what is going to be analysed), Doing (undertaking the analysis), Check (that what has been done was correct) and Acting (taking action to improve based upon the fndings).

e-mail: Anne.emmett@gosh.nhs.uk

© The Author(s) 2021 43

M. Aljurf et al. (eds.), *Quality Management and Accreditation in Hematopoietic Stem Cell Transplantation and Cellular Therapy*, https://doi.org/10.1007/978-3-030-64492-5\_6

A. Emmett (\*)

BMT, Blood, Cells and Cancer, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK

**Standard B1.1.1:** The Clinical Program shall demonstrate common staff training, protocols, Standard Operating Procedures, quality management systems, **clinical outcome analyses,** and regular interaction among all clinical sites

#### **Definition:**

**Outcome analysis:** The process by which the results of a therapeutic procedure are formally assessed

**Evidence:** Regular interaction. Regular interaction means meetings and conferences that are regularly scheduled, multidisciplinary, involve all clinical sites, and are documented in meeting minutes, including documented attendees. Regular interaction should involve physicians, nurses, coordinators, social workers, education consultants, processing staff, collection staff, and others.

This should include regularly scheduled conferences for topics such as morbidity and mortality, quality assessment and improvement, protocol development, journal clubs, patient assessment and evaluation, **patient outcomes,** tumour boards, continuing education presentations, interesting case presentations, etc.

Such topics could also be reported in joint manuscripts or abstracts for national meetings. The inspector should check attendance to confirm that all sites are represented, and that attendance is documented.

**Fig. 6.1** Sample standards from v7

#### **Standards**

There are 146 incidences of the word 'outcome' or 'outcomes' within the seventh standards, so it is present in many of the standards, or explanations of standards, or evidence required (Fig. 6.1).

As the standards mature, into the eighth, ninth, and tenth standards and beyond, it can be expected that the need to present outcome improvements will become more prevalent, so the ability to document and review these key performance indicators (KPIs) will become more essential.

#### **Collecting Data**

When collecting data, be clear to identify which patient groups/subgroups are being included. Data will normally be collated from patient notes/records/care plans.

Outcome analysis, in line with the standards, can be diffcult to establish, but the fundamental requirements are arguably quite simple:

	- 100-day mortality
	- Time to engraftment
	- Recipient outcome after infusion of a product with a positive microbial culture


**Table 6.1** Sample of data presentation[2]

Have outcome data as a standing item on the quality management/clinical governance meeting

Quality indicators include CAR-T/IEC and other novel therapies.

	- Labs
	- Wards
	- Outpatients
	- Apheresis
	- Pharmacy, etc.


**Table 6.2** Sample of data presentation[2]

**Fig. 6.2** Sample of data presentation [2]


#### **Table 6.3** New KPIs [2]

Over time a comprehensive tracking system can be established (see Fig. 6.3). To collect data, consider the following:


**Fig. 6.3** Long-term trending review engraftment [2]


Holistic outcome analysis can also be completed; these tend to be more subjective and completed via questionnaires or interview. Ideally these should have a process for scoring to facilitate analysis, for example using a scale of 1–10 for pain and satisfaction with ward facilities.


Staff-based outcome analysis can be completed by establishing a suitable internal level of completion and then assessing the following:


#### *Establishing Outcome Analysis for Novel Applications*

As each new development comes into implementation in the clinical environment, a new set of outcome analysis needs to be developed. One of the more recent of these is CAR-T/IEC. In development with the manufacturer, a new set of KPIs was developed (Table 6.3) and is being monitored as part of 'business as usual'. Once suffcient data has been gathered, the most indicative KPIs can then be used and the remainder used for audit purposes.

#### **Reviewing Data**

Outcome reviews should be completed with a wide range of staff and at regular intervals. It is a JACIE standard B/C/D 4.17 (seventh Standards) that the programme director, or designee, shall review and report to staff quality management activities, at a minimum, quarterly (Table 6.4). This presents a local snapshot of activity.

The director shall annually review the effectiveness (outcomes) of the quality management program. An annual report is required by JACIE – so combine the two.

Whilst these are useful, it is critical to look at long-term trending when reviewing outcome data. A failure to do this can result in critical trends not being spotted.

This clearly shows outliers that can be investigated.

It could be 'assumed' from Fig. 6.4 that treatments should not take place in February as two out of 3 years show high pre 100-day mortality. However, a greater depth of investigation is required to determine the causes of this.

As with all reviews, a thorough investigation should take place of any outliers. Reviews can take the form of [1]:


**Table 6.4** Sample of quality summary report [2]

**Fig. 6.4** Long-term review mortality [2]

	- Simple action development of patient guide and other information as suggested from patient survey
	- More complex such as revalidation of stem cell machine or discussion with supplier re-ongoing breakdown problems
	- Testing of machine against several components
	- Changes to donor clearance forms at registry totally in your control

#### **References**


## *Further Reading*


**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

# **Chapter 7 Personnel Requirements Including Job Descriptions**

**Songul Tepebasi and Ilknur Kozanoglu**

# **Introductıon**

Workforce is central to safe and effective delivery of cellular therapy. Staff organisation and collaboration are essential for successful outcomes [1]. It is important to defne the roles of key personnel and their support personnel, thus ensuring that tasks are uninterrupted. The number of personnel should be determined in accordance with demand, as well as the nature of the respective centre's activity. Cellular therapies are unique, in that they require many personnel with varying qualifcations and competencies to work as a team. For these therapy centres to achieve their goals, employees must work together harmoniously; this requires communication and collaboration among employees [2].

To establish mutual understanding and cooperation between components of hematopoietic stem cell transplantation (HSCT) programs, it is imperative to establish a centralised and active communication network. Motivation is another factor that ensures effective and effcient employees. Training, organisation, management, and development of personnel should all be prioritised within the quality management plan, alongside regulations that ensure the occupational safety and health of workers for all processes [2–5].

S. Tepebasi (\*)

I. Kozanoglu Department of Physiology, Baskent University Medical Faculty, Ankara, Turkey

Adana Adult Bone Marrow Transplantation Centre, University of Baskent, Adana, Turkey

Department of Quality Management, Adana Adult Bone Marrow Transplantation Centre, Adana, Turkey

#### **Organisational Structure and Organisational Chart**

The organisational structure is a coordination system that enables individuals to realise their goals by combining their respective efforts, knowledge and abilities through collaborating with others, as well as through development and execution of a structure considered most suitable to achieve a specifc goal. While developing the organisational structure in cellular therapy centres, the hierarchy, collaboration and communication of all units both within and outside the centre must be easily understood [3–5].

The organisational chart should defne, maintain and work with the optimal number of staff in the quality management system. Each level in the chart should consider the tasks, capabilities, responsibilities, and communication networks shaped within the framework of business processes and corporate systems. The scheme should refect quality management, along with clearly defning the roles, authority, responsibilities and duties of all employees [3–5].

In centres that provide cellular therapy services, organisational charts should never be made for individuals; they should be developed for units as a whole. This includes the organisational structure of all units involved, such as clinical units, cell processing, peripheral blood or bone marrow collection units, other disciplines (e.g., consultants), supporting units (e.g., medical/nutritionist) and administrative units (e.g., transportation unit and housekeeping), alongside all units with a service level agreement. Organisational charts should be developed in accordance with targets, systems and processes; staff should be chosen for positions within the chart, based on their qualifcations, competencies and training. This is necessary, as the performance of a centre is directly infuenced by its organisational structure [3–5].

The quality management system should be able to accommodate fuctuations in personnel and cover planned and unplanned unavailability to maintain operations on a day-to-day basis, e.g. illness, annual leave and departures [1–5]. Succession planning for key position should also be considered, e.g. quality manager (1). Education, quality and motivation of personnel are the most important factors for ensuring well-organised human resources and quality awareness within cellular therapy centres.

#### **Key Personnel**

All personnel involved in the planning, management and control of critical activities, both directly and indirectly, in the feld of cellular therapies should be defned as key personnel. For example, these personnel would include individuals performing stem cell collection, processing and freezing procedures. This defnition will determine in advance when and what individual cellular therapy centres can provide, along with the personnel available within the centres.

It is necessary to ensure that personnel designated and appointed conform to the requirements and qualifcations of the job to be undertaken. In addition, the experience and abilities of individuals should be considered during the selection; those selected should be trained in accordance with their duties. Designated key personnel should remain unchanged wherever possible; supervisors of key personnel should be trained to an equivalent standard, such that where key personnel are not available, those supervisors may step into the role as necessary [3–6].

#### **Personnel Competency**

Haematopoietic cellular therapies have complex and dynamic treatment pathways. All employees working in the feld of cellular therapy should therefore be developing and improving skills and knowledge through continuous training [6]. As such, competencies of employees should be measured and recorded regularly within the quality management plan (Standards B3, C3, CM3, D3) [5]. The ability of employees to work effectively provides an indicator of the quality of training, its relevance to the requirements of employees in their respective roles and whether the system is working correctly with expected results. Various methods can be used to measure the adequacy of employees for a given role. A table completed through measurement or observation can be used; electrical monitoring systems can also be used (Table 7.1).

#### **Responsibility and Task Awareness**

Once recruited, personnel are given powers and responsibilities required to perform in their given roles. Individuals must know and understand their role, to whom and to what extent they have authority, and to what extent they can give instructions to others who rely on them. To achieve this, job descriptions should include relevant duties, necessary qualifcations, responsibilities and authority.

#### **Use of Effective Communication**

Cellular therapy centres function as a multidisciplinary unit with other components within the same hospital and/or program, as well as with other centres both inside and outside of the country. To achieve this objective, interaction, cooperation between units and a common language are proven elements for success in the feld. It is vital for all personnel involved in the process to possess good communication skills and be able to use communication resources effectively. Communication meetings with all personnel and key personnel involved in the processes should be


**Table 7.1** Sample personnel performance form

scheduled regularly. These multi-unit meetings should be recorded and presented within annual reports [3–5].

All personnel should undergo annual appraisal of performance and other key aspects of their work and relationships with others in the team, with appropriate action taken in order to promote team work and good practice and maximise quality for product safety and, ultimately, patient and donor beneft [7–8].

#### **Job Descriptions**

The roles of personnel included in the organisational chart of cellular therapy centres must be clearly defned in advance. Processes within cellular therapy centres are complex; as such, any errors that may occur must be minimised. Accordingly, European Union Directive 2006/86/EC states that all personnel working in the feld of cellular therapies should have clear, documented and up-to-date job descriptions; moreover, their duties and responsibilities should be clearly documented and understandable [9].

International standards also require that current job descriptions be documented within the audits and that employees have received training for their respective job descriptions [5]. If employees have been given responsibility for a critical procedure, they must possess suffcient competencies to fulfl this responsibility. In addition, the level of authority should not be less than or greater than that required for the responsibility; the task designation of the employee should be suffciently detailed in the job description. This should detail the positions of employees within the organisational chart [3–5].

Job descriptions must be written, understandable, and clear. When employees read their job descriptions, they should not have to guess or interpret meanings beyond those which are written. Job descriptions should be concise, defne the current position and possess a dynamic structure. They should not restrict the employees in their tasks, but should allow the employees' experience to inform the work that each member performs. While creating a job defnition, it is necessary to determine the nature of the proposed task and who will write the task description. The author should be competent and knowledgeable regarding the task and how it will function. When the defnition of the task is initially formed, ideas should be collected from employees by means of interview or survey. It may also be useful to examine job descriptions created for similar positions in other institutions [10].

When a job defnition is created, it should be properly documented. All job descriptions should be reviewed and approved by the relevant centre or unit director. The director should convey the fnal defnition of the task to the relevant personnel; the relevant personnel should then be trained accordingly. The personnel must be confrmed to fully understand the content of the job description. An examination, observation or similar method can be used for this confrmation [10].

The structure of the job description may vary among centres; however, all job descriptions within an organisation should have a standardised appearance [10].

The following topics should be included:


**Signature lines** Signatures are important in validating the job description. They indicate that the job description has been approved and that the employee understands the requirements, essential functions and duties of the position. Signatures should include those of the supervisor and of the employee [10].

## **Personnel File**

Personnel fles should be created for uninterrupted monitoring of all key personnel in the quality management system. When no longer required, these fles should be archived in a secure area for the period specifed in the quality plan. Personnel fles are confdential and should therefore be kept with controlled access. These fles include personal education information, training participation and personnel qualifcation evaluations. Related documents should be included; when the employee leaves the unit, their fle should be retained [3–5].

## **Conclusion**

An important responsibility of directors working in cellular therapy centres is to understand and defne the roles and responsibilities of employees so that their objectives are best met. This enables directors to better distribute workload to personnel appropriately, whilst maintaining safety and effciency. The collection of personnel or staff satisfaction surveys at regular intervals is recommended. The results should be evaluated at the quality committee meetings or similar groups with the goal of optimising ongoing processes and operations as well as workforce well-being.

A continuously improving quality management system incorporating the correct personnel with clear roles, responsibilities, training, competency and working relationships will ensure that processes are effective and effcient and maintain safety and quality for the programme. Processes are numerous and diverse; personnel should have continuous development of skills and qualifcations, and key personnel should continuously contribute to the training, competency and personal development of new and existing personnel. Continuity and robustness of operations should be supported by cross-cover arrangements and succession planning. All of these aspects are covered by FACT-JACIE standards and the accreditation process, which should be used as an opportunity to review personnel and their functions, and, where necessary, identify defciencies or weaknesses, undertake corrective actions or highlight issues to the accreditation organisation and external inspectors during the accreditation process.

#### **References**


**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

# **Chapter 8 Third-Party Agreements**

**Anne Emmett**

# **Gentlemen's Agreement**

In the past, many issues were resolved following discussion and a handshake between two parties (Fig. 8.1). Nothing was written down and progress depended on continued verbal agreement. In some cases, the reason for the original agreement is lost and things just 'carry on'. This is NOT acceptable within JACIE, nor any professional environment.

# **Memoranda of Understanding (MoU)** [1]

This is a more formal written arrangement between two, or more, parties. It may take the format of a completed form with basic information, or may just be a formal letter, but would be signed by both parties.

A MoU (Table 8.1) can be the frst step in establishing a process or partnership. However, MoUs are not legally binding and so cannot be deemed to be a suitable process for maintaining services between parties. They do indicate a degree of seriousness and mutual respect. They imply that a formal written contract, agreement – either technical or third party – or a service-level agreement is to follow.

A MoU can be assessed as a 'frst step' towards a formal agreement. It can be terminated without legal consequence in most circumstances.

e-mail: Anne.emmett@gosh.nhs.uk

© The Author(s) 2021 61

A. Emmett (\*)

BMT, Blood, Cells and Cancer, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK

M. Aljurf et al. (eds.), *Quality Management and Accreditation in Hematopoietic Stem Cell Transplantation and Cellular Therapy*, https://doi.org/10.1007/978-3-030-64492-5\_8

#### **Table 8.1** Outline of MoU


Name of contracting organisation: Address:

**Fig. 8.1** Gentleman's Agreement

#### 8 Third-Party Agreements

**Fig. 8.2** Contract

#### **Contract/Commercial Agreement** (Fig. 8.2)

A contract is the main document governing the deal between you and another organisation. It is the written formal agreement between the two parties. It stipulates each party's legal responsibilities, obligations, governance, contract length, fnancial details and liabilities within the agreement. It will include the commercial agreements and does not go into the purely technical aspects of the manufacturing, supply or outsourcing of the product or process (Table 8.2). Where possible, sections should not be reproduced in multiple documents, as this can lead to contradictions and conficts. Where appropriate, cross references to relevant sections in different documents should be made.

As such, it is typically drafted by the legal, fnancial and management teams of the contractual parties.

#### **Service-Level Agreements (SLAs)**

An SLA focuses on measuring performance and quality, as agreed between you and another organisation. The SLA should not determine governance arrangements, fnancial arrangements, contract lengths, etc. (see Contract section), though these are often incorrectly included in SLAs, making the SLA very long and overcomplicated.

Creating an SLA as well as a contract allows you to revise the SLA without changing the contract. Though the contract may be for 5 years, the SLA may be reviewed and amended as frequently as required and at least every 2 years for JACIE.

The SLA (Table 8.3) should include a description of the services to be provided and their expected service levels, metrics or key performance indicators (KPIs) by which the services are measured, the duties and responsibilities of each party, the remedies or penalties for breach, process for disagreements and a protocol for adding and removing metrics.

**Table 8.2** Typical contract contents


**Table 8.3** Typical SLA contents


#### **Technical Agreement**

A technical agreement (Fig. 8.3) (also known as a quality agreement) is a written contract that is required whenever you outsource an activity covered by quality guidelines – often good manufacturing practice (GMP) guidelines for pharmaceutical products, but equally JACIE, HTA, FACT and other national and international quality standards. It sets out the quality management responsibilities of each of the parties, both quality control and quality assurance (Table 8.4).

Even though there is an outsourcing of a process, the organisation contracting the process is still accountable for outcomes and is therefore responsible for the activities of the contracted organization. Make sure there is involvement in change control, including assurance that any appropriate validation and qualifcation are carried out and documented; that there is involvement in any major or critical investigations, and in any other critical issues that require both parties' input; and ensure that the level of involvement is detailed in the Technical Agreement. The contracting organisation needs to also defne how often there will be audits, or audits requested, and if it is intended to send in an independent auditor; this too needs to be specifed.

**Table 8.4** Typical technical agreement


The technical agreement spells out the *technical specifcations and responsibilities* of the parties required for the technical or outsourcing activities and processes. It is to ensure compliance with various QC (quality control) and QA (quality assurance) requirements of the technical process or the outsourcing [2].

It is typically drafted by the technical teams in each organization. It is not usually necessary to get legal advice on a technical agreement because a lawyer will not usually be able to advise on the actual details of a technical agreement.

#### **Third-Party Agreement**

Third-party contracts are agreements that involve a person who is not a party to the contract but is involved with the transaction. This could, for example, be that an organisation is contracted to carry out viral analysis in which case the organisation will then contract the staff to do the work. The staff completing the viral analysis have not directly signed the contract but are involved with the transaction. This can get very confusing within the clinical environment if the staff doing the work also have honorary, or permanent, contracts with the contracting organisation.

#### **Quick Checklist** [2]

*The contract should always refer to the technical agreement for technical matters* related to quality control and assurance. As such, the technical agreement should not contain "legal" or "commercial" terminology.

*No duplication of provisions should relate to the same subject matter*, so that one document simply refers to the relevant provisions in the other document, i.e. instead of repeating or restating the same thing. This is to avoid accidental conficts or contradictions.

*There should be consistency in nomenclature, defnitions, and duration* such as the same name of the parties in both documents, the same process, the same defnitions for terminology and expressions, and the same duration of each agreement.

*There should be no "legal" or "commercial" terms in the technical agreement*. The job of the technical agreement is to set out technical parameters. It is not intended to set out the commercial relationship between the parties that should go into the contract instead.

That means that the contract is the right place to cover things like patient confdentiality terms, warranties, indemnities, liability limitations, pricing, scheduling, etc.

#### 8 Third-Party Agreements

#### **Fig. 8.4** Communication

#### **Communication Is Critical** [3] (Fig. 8.4)

Defne:


Make sure that the contacts are clear to both parties and that their communication channels are open.

Ensure there are nominated single points of contact in each organisation for key matters, plus 'local' contacts as required, e.g. HTA lead, quality manager, service manager, accounts. Ensure that, where necessary, there are secure email connections, or use encryption for any emails containing personal or patient data. Ensure this is made clear in all joint documents.

Try to avoid 'scatter gun' communications between the organisations when setting up the agreement and then running the process as this can lead to either key communications being lost or email overload. When necessary, have face-to-face meetings, even if this is by video conference.

## **References**


**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

# **Chapter 9 Performance Measurement**

**Amal Alseraihy, Waleed Rasheed, and Mahmoud Aljurf**

Accountability and performance are vital pillars in healthcare organizations as both are key factors on the platform of global initiatives in healthcare and monitored through the management of performance measurements. In the context of rising healthcare expenditure, performance measurement (PM) is becoming increasingly integral to accountability. Healthcare accountability mechanisms have traditionally included business planning, annual reporting, and contracting. In recent years, a richer sense of accountability has emphasized the achievement of goals effectively and effciently and has stimulated the growth of PM. PM has been described as "the use of statistical evidence to determine progress towards specifc defned organizational objectives" (State of California 2003) [1]. The literature includes reports on performance measurement initiatives across the healthcare spectrum from primary through tertiary health care and public health and the voluntary sector, many driven by the backend as a reactive response to demands from governments, consumers, other payers, proponents of evidence-based practice, and accreditation organizations [2]. Substantial resources, by various organizations, have been invested in PM system development from policy level to front-line care delivery.

Performance measurement (PM) in its simplest form is the "measurement of performance": the regular and continuous assessment of whether the current processes or practices in place are accomplishing the goals and objectives created, implemented, and monitored to sustain the organization, company, or program" [3].

A. Alseraihy (\*)

W. Rasheed · M. Aljurf Oncology Center, King Faisal Specialist Hospital & Research Centre, Riyadh, Kingdom of Saudi Arabia e-mail: wrasheed@kfshrc.edu.sa; maljurf@kfshrc.edu.sa

© The Author(s) 2021 69 M. Aljurf et al. (eds.), *Quality Management and Accreditation in Hematopoietic Stem Cell Transplantation and Cellular Therapy*, https://doi.org/10.1007/978-3-030-64492-5\_9

Department of Pediatric Hematology Oncology, King Faisal Specialist Hospital & Research Centre, Riyadh, Kingdom of Saudi Arabia e-mail: aseraihy@kfshrc.edu.sa

Utilizing well defned measures will promote a culture of continuous growth and development, both clinically and operationally. Such necessity for PMs is the same for a stem cell transplant program – to ascertain and continuously monitor processes that function within the program from fnancial to operational to clinical aspects. PM is the process and performance measures are the drivers used to establish the level of success or need for improvement (Fig. 9.1).

SCT is a highly specialized and cost-driving service, operating at multiple levels of structures and processes, according to each program's capacity and complexity of treated cases. Whether the focus of the program is to achieve excellence or to build a quality system or to comply with national or international accreditation, performance improvement and management can be challenging for the decision makers without objective customized performance measures for such complex medical care. The frst part of this chapter will provide the reader with a comprehensive review of performance measurement defnitions, development, and working framework. The second part will focus on performance measurement in SCT program.

## **Defnitions for Healthcare Performance Measurement**

**Performance measurement** In general terms, it can be defned as the regular measurement of outcomes and results, which generate reliable data on the effectiveness and effciency of various aspects of an organization that keep it afoat.

**Input** Resources (human resources, employee time, funding) used to conduct activities and provide services.

**Activity** Individual tasks funded by projects or programs.

**Output** Products and services delivered. Output information does not tell you anything about the actual results achieved or the consequences of the products and services delivered. Output information is important to show the scope or size of what the inputs and activities produce.

**Outcome** An outcome represents a specifc result a program is intended to achieve. An outcome can also be defned as the specifc objective of a specifc program or service. An outcome is not what the program produced itself (the output), but the consequences of those products, services, or assistance. It is important to distinguish between end outcomes (objectives), on one hand, and intermediate outcomes (intermediate results), on the other.

**End outcomes (objectives)** This is the highest-level objective toward which a program works. The end outcome is what the program is designed to ultimately achieve: which should be the most "ambitious" outcome or result program managers can materially affect or infuence and for which they are willing to be held responsible.

**Intermediate outcomes (intermediate results)** An intermediate outcome or intermediate result is a critical outcome or result that must occur in order to reach the higher-level, end outcome/objective. As the PM process advances, it is important to understand the necessity to obtain and act on the intermediate outcome or result before achieving the end outcome/objective.

**Indicators** An indicator is an instrument that helps you measure change over time. It is important to remember that end outcomes and higher-level objectives require higher-level indicators. Intermediate outcomes/results require lower-level indicators. Indicators can be quantitative, or qualitative, or a hybrid of the two.

**Performance indicator or key performance indicator (KPI)** A quantifable measure used to evaluate the success of an organization, employee, etc., in meeting objectives for performance.

## **Measure Development Life Cycle**

Figure 9.2 illustrates the fve phases in measure development life cycle. Although the life cycle shows each phase as a discrete activity, the measure life cycle is dynamic. Some phases may overlap or take place concurrently or result in feedback with earlier phases [4].

**Conceptualization** Develop measure concepts and then narrow down to specifc measures. The developer conducts an environmental scan and requests input from a broad group of stakeholders, including patients.

**Specifcation** Identify the population, the recommended practice, the expected outcome, and determine how it will be measured.

**Testing** Assess the suitability of the quality measure's technical specifcations and acquire empirical evidence to help assess the strengths and weaknesses of a measure.

**Fig. 9.2** Example for performance measure life cycle; https://www.cms.gov/Medicare/Quality

**Implementation** Identify measures to submit for selection and rollout processes.

**Use, continuing evaluation, and maintenance** Ensure that the measure continues to add value to quality reporting measurement programs and that its construction continues to be sound.

The Centers for Medicare & Medicaid Services (CMS) uses the following decision criteria throughout the measure development cycle to ensure that a measure meets the applicable standards before moving to the next phase:

**Importance to measure and report** including analysis of opportunities for improvement such as reducing variability in comparison groups or disparities in healthcare related to race, ethnicity, age, or other classifcations.

**Scientifc acceptability** including analysis of reliability, validity, and exclusion appropriateness.

**Feasibility** including evaluation of reported costs or perceived burden, frequency of missing data, and description of data availability.

**Usability** including planned analyses to demonstrate that the measure is meaningful and useful to the target.

#### **Measure Development Process**

#### *Bringing It All Together*

As previously stated, in this chapter, performance measurements for stem cell transplant programs operate, as they do, in general with all standard healthcare organizations, ensuring that all indicators and measures directly link to the organizations' strategic objectives, mission, and vision statement – utilizing key performance indicators and the approach of Donabedian's three domain quality framework of structure, process, and outcome measures [5]. Such is the case when conceptualizing the framework to construct, pilot, implement, and monitor stem cell transplant performance measures, ensuring that the critical key performance indicators that are essential to your operational strategic plan and also drive your measures.

Before one can create and implement measures or indicators, you should determine who your key stakeholders and process owners are as this is as important in determining your measures/indicators. These are those individuals who will work to bring to fruition your desired outcomes after you perform your intense education sessions with them and to provide the knowledge and training needed to meet the target set for your measures or indicators.

To begin with each measure or indicator is intentionally chosen through the process of conducting an RCA (Research, Compare, & Act), which begins with a rigorous internal research to determine specifc programmatic needs, performing external literature reviews to determine best practice, and applying your fnding in research to compare your current state with the desired state (Fig. 9.3).

**Fig. 9.3** SCT performance measurement RCA framework

Once you have accomplished your research, compared your fndings, determined what you need, your team is now ready to agree on the design of the selected qualitative and/or quantitative measure/indicator, determine your data source and collection frequency, create and validate a standardized data collection tool and perform a sample collection to test your tool. If the data tool collects what you designed and desired, perform a real data collection session. If not, go back to the drawing board, assess your tool, determine the cause, and make the revisions, as needed. You will not be able to move forward until your data collection tool is considered valid and confrmed as effective to collect the data it was designed to collect. Once you have collected your data, you are now you ready to Act: bring the outcome of your arduous work to action by performing an analysis on your data. Once your data has been analyzed and your targets set based on your current and desired state, you are now ready to develop your roll-out plan and schedule your action. First, disseminate your fndings to your stakeholders and process owners to get them ready for your upcoming education and training sessions. A well-informed team is a well-equipped team and ready to assist you to shape the culture for success. It is now time to perform your educational sessions indicating your fndings, beginning with the RCA, propose the plan to move forward and ensure to involve your team in continuous monitoring by setting champions in each area. If you have obtained your goal you will need to sustain the gain. If improvement is needed, use your well-informed team champion to perform continuous monitoring, education, and training until desired outcome is achieved.

As you now have set your data collection schedule, you will need to adhere to this to ensure continued success. Create dashboards or scorecards (Tables 9.3 and 9.4) to maintain intentional active continuous monitoring, allowing you to promptly act to any measure or indicator that may fall beyond the set target.

#### **Performance Score**

In most cases, at its basic level, a performance measure is a ratio. The denominator represents the number of eligible cases, less any exclusions or exceptions, and the numerator represents the number of instances the clinical action of interest was performed. It is helpful to note that the denominator is often derived from, and sometimes equal to, an initial population; this initial population is the broadest grouping (e.g., all patients age 14+ with transplanted specified diagnosis). The initial population can be reduced to a denominator (e.g., all

**Fig. 9.4** Anatomy of a performance measure

initial population patients that underwent transplant) and then to a denominator with exclusions and exceptions removed. Figure 9.4 below visually depicts the anatomy of a performance measure from an arithmetic perspective.

#### **Goals for Measure Development in SCT Program**

A critical aim of any stem cell transplant center or program is to ensure that such measures are directly aligned with the mission and vision statement of the healthcare organization in which it dwells. In addition, safeguarding the process within performance measurement affords one the ability to assess the current state, benchmark with competitors, ensure continuous assessment for improvement opportunities, ensure accrediting governing body's continuous readiness, and monitor growth and development: internal assessment for an external cause corporately and publicly. Some challenges with PM in SCT can be the substantial variations in SCT center characteristics; centers have different care models to optimize the use of available resources, identifying external benchmarks and utility of comparative external benchmarks. However, the primary purpose of quality measurement is to identify opportunities to measure and thus improve patient care and other programrelated outcomes. Table 9.1 summarizes some guiding principles for measure development.

Quality measure development remains a focus for quality assurance and value staff to continually meet the evolving needs of its members, help its members meet national and international accreditation requirements, and to provide members with information that informs clinical decision–making.


**Table 9.1** Criteria for performance measures selection [2]

# **SCT Program Performance Measure**

There are several types of performance measures, but structural, process, and outcome performance measures are the most practical and objective that can be implemented in SCT across its three dimensions: clinical, collection, and processing. Table 9.2 outlines some of these performance measures, their defnitions, and examples for their indicators in SCT program.

**Structural measure** Structure of care is a feature of a healthcare organization or clinician related to the capacity to provide high-quality healthcare. Structure measures are supported by evidence that an association exists between the measure and one of the other quality domains.

**Process measure** A process of care is a healthcare-related activity performed for, on behalf of, or by a patient. Process measures are supported by evidence that the clinical process, which is the focus of the measure, has led to improved outcomes. These measures are calculated using patients eligible for a service in the denominator and the patients who either do or do not receive the service in the numerator.


**Table 9.2** Example of performance measures and indicators in SCT

**Outcome measure** An outcome of care is a health state of a patient resulting from healthcare. Outcome measures are supported by evidence that the measure has been used to detect the impact of one or more clinical interventions. Measures in this domain are attributable to antecedent healthcare and should include provisions for risk adjustment. The outcome of performance measurement processes should result in improved value. Value in the part of health care domains:



**Table 9.3** Sample of annual operational dashboard

#### **Performance Measurement and KPI**

In its simplest form, a key performance indicator (KPI) is a type of performance measurement (PM); these are the critical (key) indicators of progress toward an intended result. KPIs provide a focus for strategic and operational improvement, create an analytical basis for decision-making, and help focus attention on what matters most.

Goals of an organization should set the focus of your quality, productivity, and fnancial metrics. The term "metric" means the same as a KPI to some, but to others, it means a collection of related measures that when placed together become a metric. Some have used metrics and KPIs for staffng needs, position justifcations, quality assurance, revenue cycle, and strategic planning in various hematopoietic cellular therapy (HCT) programs. Various challenges discovered in implementing a PM within HCT programs are due to the substantial variation in the characteristics of HCT centers that have different care models to optimize the use of available resources, identifying external benchmarks, and the usefulness of comparative external benchmarks.

# **The Value of Dashboards for Metrics or KPI**

Provide a user-friendly, visual summary of operational and clinical information.


KPIs can result in great limitations when used without setting in place operational effectiveness goals; however, goals should drive what you are measuring but measures should not drive goals. The question is: what are HCT centers or programs trying to assess and analyze? Here are some examples for initiative and strategic goals:


# **Dashboard Basics for Quality** (Table 9.4)



**Table 9.4** Sample of scorecard metrics


# **Challenges HCT Programs Can Embrace**


# **Examples of Quality KPI for Clinical SCT Program**

(Table 9.5)



**Table 9.5** Sample of template for SCT quality KPI


# **KPI Administrative Focus Areas**


# **Conclusion**

Performance measurement offers policy-makers in SCT program a major opportunity for improvement and accountability. Securing improved performance measurement often requires active leadership and it should aim to improve the quality of decisions made by all actors within the program. It is important to emphasize that the presentation of performance measurement data and how this infuences its interpretation by patients, providers, and the public require more attention, as public reporting has many benefts but can lead to adverse outcomes; mechanisms should be put in place to monitor and counteract these adverse outcomes.

#### **References**


**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

# **Chapter 10 Tracking and Traceability**

**Lex Van der Gouw**

## **Introduction**

In the global feld of cellular therapy, including stem cell transplantation, traceability of the cellular product is of essential importance to be able to ensure the patient's safety [1]. During the process of donation, transportation, processing and infusion, storage, or disposal, it is critical that the product can be traced from donor to patient and vice versa. Also, in case of any adverse event, such as poor or non-engraftment or infection, traceability is paramount.

Unambiguous identifcation of a cellular product can only be achieved through unique donation identifers and uniform, standardized product description. Stem cell products are regularly transported across national borders, thus creating the need for international agreement on product descriptions and unique donation identifcation.

Another key element in traceability and identifcation of cellular products is the transfer of product information. To further enhance safety, accuracy and effciency, increasing numbers of facilities use electronic systems. Transfer of information between such systems also requires international standardisation of electronic donation and product information.

In compliance with the JACIE standards, standardisation and encoding of cellular product descriptions shall be performed according to the ISBT 128 standard terminology or the EuroCode standard.

In this chapter, the basic principles and means to standardisation of product information will be discussed, using the ISBT128 standard as an example. However, these basic principles also apply to the EuroCode standard [2].

L. Van der Gouw (\*)

Cell Therapy Facility (CTF), University Medical Center Utrecht, Utrecht, The Netherlands e-mail: agouw@umcutrecht.nl

<sup>©</sup> The Author(s) 2021 83

M. Aljurf et al. (eds.), *Quality Management and Accreditation in Hematopoietic Stem Cell Transplantation and Cellular Therapy*, https://doi.org/10.1007/978-3-030-64492-5\_10

## **Information Environment**

Several elements are necessary to create an environment in which information is standardized and transferable between facilities on a global level [1]. Together these elements form the information environment (Fig. 10.1).

The base element is terminology. Without a common international understanding of product descriptions, further attempts to standardisation are useless.

Standardisation in terminology is required to be able to make a distinction between variations in the following product characteristics:


Product descriptions vary between facilities, nationally as well as internationally. Variations may relate to, for example, storage temperature, the amount of DMSO used in cryopreservation or additional additives after processing. Standardisation in terminology needs a high level of detail to provide the means to make a distinction between different products or track alternations to a product. Once an international consensus in terminology is achieved, this information can be used to generate a product description, based on the three characteristics as mentioned above.

This information should be managed with great care and be accessible to users around the world.

So, with a consensuson terminology, the next layers in the information environment are the reference tables in which this information is stored. With the provided accessibility, facilities around the world are now able to defne their products. By combining this standardized information, a unique description of the product is achieved, which can subsequently be uniquely encoded.

#### **Example 1**

An autologous apheresis product which is frozen in 10% DMSO solution, with no other additives:


Together this would generate the unique product description:

• HPC, APHERESIS|Citrate/XX/<=−150C|10% DMSO|Cryopreserved|Mobilized

#### **Example 2**

An allogeneic bone marrow product enriched for mononuclear cells (MNC) with added human serum albumin


Together this would form the unique product description:

• HPC, MARROW|None/XX/refg|3rd Party Comp:Yes|Mononuclear cell enriched

With the unique product description in place, now one must be able to transfer this information electronically. To achieve this, the product description needs to be converted into a unique, electronically readable, product code and a delivery mechanism is needed, the next two layers in the information environment. Product codes provide the structure and context to be able to decode them to meaningful information. They also provide the link to the reference table so that each product code can be traced to the corresponding product description. Next to the product description, the product code must encode whether or not the product has been divided into separate containers (e.g. a cryopreserved autologous product). Only then, each separate product bag can be traced regarding storage and infusion.

The most commonly used delivery mechanism to transfer information electronically is the linear barcode. As the information that a linear barcode can contain is limited, delivery mechanisms with a higher capacity are also available such as 2D (data matrix) codes. A single data matrix code can hold the same amount of information as several linear barcodes, as shown in Fig. 10.2. The use of a data matrix code is therefore more effcient, especially on smaller labels, and will contribute to a safer and more reliable transfer of electronic information. By using a universal delivery mechanism, such as a barcode, information can now be exchanged between different electronic systems on a global scale.

In the last layer, all previous elements come together to generate a label that contains all the information, eye-readable and electronic, necessary to identify the product and to be able to process that information to maintain traceability. Standardizing the label format and layout such that critical information is placed at


**Fig. 10.3** Standardized ISBT128 label format [3]

fxed positions, as shown in Fig. 10.3, greatly reduces the risk of errors in the interpretation and (electronic) transfer of information.

#### **Donation Identifcation**

Product coding alone, however important, is not suffcient in the unique identifcation of a cellular product. Without the ability to uniquely trace the donation of a cellular product to the original donor, product coding is meaningless.

Unique identifcation of a donor is hampered by the sheer number of volunteer donors as well as different donor identifcation strategies used by international centres [4]. To further enhance safety and reliability in donor identifcation, the WMDA (World Marrow Donor Association) has developed a global donor identifer (GRID). The GRID comprises identifying information about the facility issuing the GRID and a donor identifer.

Next to unique donor identifcation, the donation itself also needs a unique, uniform identifcation.

Similar to the GRID, the donation information contains a donation sequence number and identifying information about the facility that issued the donation number, e.g. a collection facility or registry. In the ISBT 128 coding standard, the year in which the donation took place is also embedded in the donor identifcation number.

#### **Combining Donation and Product Information**

In April 2017, legislation became effective to apply the Single European Code (SEC) on tissue and cell products in compliance with Directive 2004/23/EC of the European Parliament. The purpose of the SEC is that donation and product information are represented in a consistent, combined manner, further aiding the traceability of such products. Basically, the frst part of the SEC contains the donation information (facility, sequence number) preceded by a country identifer. The second half contains the product information including a split number and the expiry date. Where the donation identifcation sequence will not change, the product information sequence changes when the core state of the product is altered.

If necessary, products imported from outside the EU for distribution within the EU will be assigned a donation and product sequence assigned by the importing tissue establishment in order to be able to create an SEC. Records of the original donation and product information and the newly assigned SEC should be maintained in order to link this information for traceability purposes.

In summary, the key elements to the effective, safe, and reliable traceability of cellular products are as follows:


#### **References**


**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

# **Chapter 11 Adverse Events and Corrective and Preventive Actions**

**Phuong Huynh and Renza Monteleone**

A very important part of the quality programme is the development of a robust system for reporting, investigating, and resolving errors, accidents, adverse events, biological product deviations, and complaints. Reporting and reviewing adverse events (AE) should not be about "blaming" individuals but about assessing if the process which may be at fault can be improved. All personnel should be encouraged to report anything which affects transplant safety [1].

Centres often used a hospital-based incident reporting system, but it may not be adequate to meet the needs of the HSCT programme. Often, not all AEs were reviewed by the programme director and/or a report was issued to the patient's physician. Other signifcant problems included those related to donor selection and testing, labelling and process control [2]. The HSCT programme should have a system in place which allows the team to follow the management of any occurrences, to propose preventive actions to avoid the occurrences that will happen in the future and to assess the effcacy of those actions.

Prevention of errors is one of the most important aspects of safety in transplantation. Analysis of potential risk factors associated with the entire range of procedures should be part of the overall transplant programme development. Every procedure should be analysed and potential risk factors identifed BEFORE they are implemented. Documentation is important to support the investigation of errors, accidents and adverse events, biological product deviations and complaints because these investigations are frequently retrospective [1]. Fundamentally, one should know *where* errors occur in the processes, *why* they occur and *how* to manage them, e.g.

P. Huynh (\*)

SPF Sécurité sociale DG- HAN, Brussels, Belgium

R. Monteleone

© The Author(s) 2021 89

Hematology Service, Institut Jules Bordet, Brussels, Belgium

Transfusion Service-Stem Cell Transplant Program, Grande Ospedale Metropolitano "Bianchi Melacrino Morelli", Reggio Calabria, Italy

M. Aljurf et al. (eds.), *Quality Management and Accreditation in Hematopoietic Stem Cell Transplantation and Cellular Therapy*, https://doi.org/10.1007/978-3-030-64492-5\_11

does quality system include a near-miss reporting system (prevention of errors) and a corrective actions system when incidents have happened?

## **Defnitions of What to Report**


## **Investigation, Analysis**

While there is no set timeline for investigation, review, and analysis, this should be undertaken quickly so that a potential repeat of the issue is avoided. This aspect should be included in internal specifc SOP.

Investigation and analysis in some centres are done through formal review of the entire process to identify where the error has occurred. Collection and processing facilities will have quality incident reporting mechanisms in place and these are shared with the clinical programme where an incident occurred across the linked process, e.g. transportation of the product from collection/processing facility to clinical facility: all parties receive the quality incident report analysis and close the incident. The investigation itself might involve looking at all documentation,


**Table 11.1** List of examples templates provided for this section

NOTE: This is not a exhaustive list


training record, having discussions with staff involved and observing the process as it happens.

The forms and reports can be categorised by type, e.g. procedure (e.g. cell reinfusion) and equipment used and then evaluated. This evaluation can be done by specifc groups or as part of one of the regular meetings, e.g. quality group. The more frequent events should be prioritised and then resolved (Table 11.1); this can be done by amending policies and procedures, implementing revised worksheets or retraining staff. By doing this, the quality programme is continuously being improved.

## **Corrective, Preventive Action**

Action taken to eliminate the root causes of an existing discrepancy or other undesirable situation to prevent recurrence. As an example, weekly meeting to review with relevant director, quality manager, chief nurse and/or medical


**Table 11.2** Example form to report deviations and near-misses; adverse events; occurrences

director and area where incidents occurred. Some centre quality group meetings have errors, accidents and adverse events as part of the standing agenda; group members should include all related facilities. Some centres have separate risk management groups.

The investigation and reporting system is a means of quickly recording nearmisses as they occur (Table 11.2). All staff are responsible for completing the forms which ask three simple questions – what happened, what immediate action was taken and what might be done to prevent recurrence of the problem. Each near-miss is categorised, e.g. products, sampling, transport, labelling, infusion, nursing, medical, drugs, pharmacy, result processing. Every day, reports are collected and on a weekly basis, the relevant director, quality manager, head nurse and pharmacy or other services as required review the documents and discuss corrective actions. Sometimes, thorough investigation is needed and this will involve observations, interviews and complete review of the procedures linked to the near-miss which took place. The results and outcomes are reported back to all departments within the programme and monthly "*Trend*" reports are written to establish whether improvements have been made and are working. Whatever corrective action is taken, e.g. amending an SOP or re-training staff, must be documented, and assessed whether it has achieved the desired impact.

#### **Biological Product Deviations (BPD)**

The most common BPDs encountered by clinical programmes involve products with positive microbial cultures or products from ineligible donors. Such products are only used by clinical programmes when evaluation shows that the benefts outweigh the risk to patient if no alternative is available.

In some cases, the relevant information is not known until after the infusion has occurred. Centres are responsible for deciding on whether they will use these products and, if so, under what circumstances. There must be a detailed plan and procedures in place which describe the following:


For methods for investigation and review where the BPD was unknown until AFTER the cellular product was infused, centres can also follow the processes above.

Investigation and analysis in some centres are done by reviewing the entire procedure to identify where the contamination might have come from. Collection and processing facilities have quality incident reporting mechanisms in place and these are shared with the clinical programme where an incident occurred across the linked process. All parties receive the quality incident report and meet to analyse and close the incident – the investigation itself might involve looking at all documentation, training records, having discussions with staff involved and observing the process as it happens.

Methods for investigation and review where the BPD was known BEFORE cellular product was infused followed the systems described above. As an example, we present a case whereby a product from an unrelated donor was potentially contaminated due to infection of the donor with a tropical disease. The collection centre advised the transplant centre only on the morning of the collection. In the meantime, at the transplant centre, the recipient was fully conditioned using full intensity conditioning regimens. The reasons behind the potential contamination

were fully investigated and revised processes put into place at the collection facility following close liaison with the clinical facility. The centre had no alternative but to use the product as no other donor was available in time. The centre quickly liaised with specialists at their own centre and external specialists in tropical diseases, and several different samples were sent to different laboratories and results returned within hours prior to cell infusion. All steps were taken to safeguard the recipient (prophylaxis), and the recipient was informed prior to, during and after infusion. Records of the entire process were documented and fled in patient case notes, incident reports, deviations and near-miss reporting with corrective actions clearly shown.

The centre where the BPD occurred BEFORE infusion should investigate the process of collection and infusion with relevant staff and report to medical director of corresponding service, and BPD incidents and reports should be audited regularly. Some centres have separate risk management groups working with all related facilities to develop procedures on how products are managed and reported in accordance with applicable regulations. Policies are in place which cover criteria for release, labelling, notifcation of recipient, investigation of cause, disposal and timely notifcation of transplant physician and other related facilities involved. Procedures are in place for dealing with BPD if unknown until infusion has occurred as per JACIE standards [4].


#### **Example 3**

#### **Example 4**


#### **Example Template 5**

# **ADVERSE EVENT AND NEAR-MISS REPORTING PROCEDURE HEADINGS STEM CELL TRANSPLANT PROGRAMME**

#### **STANDARD OPERATING PROCEDURE**

#### **TITLE: ADVERSE INCIDENT AND NEAR-MISS REPORTING**


Replaces: Revision :

INDICATIONS FOR PRACTICE

AUTHORISED PERSONNEL/TRAINING REQUIRED (Who is responsible for Reporting and what level of training is required)

PROCEDURE FOLLOWING INCIDENT/NEAR MISS:

What Actions MUST be taken and how is safety assured following an Incident or Near Miss?

WHEN PRINTED This SOP is for single use only. Please destroy following use.


# **References**


**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

# **Chapter 12 Process Indicators**

**Olga López-Villar**

# **Introduction, Defnitions, and Example**

The organization of work by processes is a strategy well established in quality in recent times. It may seem challenging to implement this in the medical feld. However, working in a process-based organization will help us establish the quality system since each process has different personnel, different procedures, different risks, controls, indicators, etc. And the interaction between those processes or subprocesses also requires particular detail.

To start with, clarifcation of some terms is needed because they may look similar [1, 2]:


O. López-Villar (\*)

Hematology and Hemotherapy Department, University Hospital of Salamanca, Salamanca, Spain e-mail: olgalopez@usal.es

M. Aljurf et al. (eds.), *Quality Management and Accreditation in Hematopoietic Stem Cell Transplantation and Cellular Therapy*, https://doi.org/10.1007/978-3-030-64492-5\_12

**Fig. 12.1** Example of a process


The process has to be validated before opening the bakery (tested to have a certain result), the equipment has to be controlled, there may be a recipet (SOP), etc.

In the process, there shall be controls to assure that the bread is almost the same every time: weight of ingredients, temperature of the oven, etc.

An indicator may be established, depending on the requirements of the clients, the controls of the product, the previous occurrences of the bakery, etc. For example, more than 95% of breads that are sold at a certain price have to weigh ≥500 g [4].

#### **Process Defnitions**

The transplant process is extremely complicated. It can be treated as a single process with different sub-processes if all the steps are performed in a single institution, or as different processes with a close relationship in case of different entities in the same or in different institutions.

For illustrative purposes, the transplant process has been simplifed (Fig. 12.2).

When a transplant program is starting in the quality and accreditation process (it is also a process) they have to work on many aspects, among them the process

**Fig. 12.2** Summary of processes in a transplant program

defnitions. They have to be based on the structure of the program, of the organization that hosts the program, responsible staff, etc.

Although it is not mandatory, the division in to at least clinical, collection, and processing processes can be a start. Those procedures shall have a clear interaction, whether being performed in the same or different institutions.

In the annual review, the indicators of the processes and other issues are included. A change to the processes may also be required within time and has to be carefully analyzed (risk assessment), planned, and implemented, to be further analyzed again.

#### **Process Controls**

The process controls are described in detail in the current edition of FACT-JACIE standards [1, 2].

CM8 – Marrow collection process controls include procedures, inventory, equipment, blood components, written order for collection, peripheral blood count to proceed, suitability prior to collection, anesthesia, mobilization, quality of the product, aseptic technique, pediatric donors, packing, fltration, and records.

C8 – Apheresis collection process controls include the ones seen for marrow collection (except for the different requirements for the fltration of bone marrow), plus some specifc controls regarding central lines.

D8 – Processing process controls include manufacture of the product, written request, specifc information for allogeneic donors, validated processing procedures, identifcation of critical control points, aseptic technique, microbial contamination, records, review of processing record, end points not met, more-than-minimal manipulation, blood group and antibody screen, cord blood, and sample storage.

Clinical program controls: Through all the chapter of clinical standards, a number of controls are indicated: control of airborne microbial contamination, document control, and outcome analysis (see Chap. 6). In fact, among the principal controls for the clinical unit are the ones described in the outcome analysis chapter and also performance measurements (see Chap. 9) and benchmarking.

A unit can require further controls, depending on the different procedures performed.

#### **Process Indicators**

#### *Selection, Defnition, and Range*

How to choose an indicator?

As indicated in the defnitions, an indicator is a measurement done in a critical point that has to be within a defned range. If not, an action should be taken. They are used to monitor the quality of the process [3, 4].

In a visual way, it is like a thermometer. If the measured value is above or below a certain level, there are no major issues, and one can continue working the same way. But if for instance the value is above that level, it is like having fever, which means that there is a problem that has to be studied and treated.

Indicators can be different among transplant programs. They have to be selected based on the risky points of the process and procedures, on the occurrences detected in the previous months or years, etc.

It is important to remember that if the indicator is not within the range, an action should be taken. For example, it is diffcult to defne the "number of transplants per year" as an indicator. It is a measure of the activity. An indicator requires an objective level. If you select as quality indicator "more than 100 transplants per year," you have to think if there is any action to be performed if a year there are 90 transplants (probably not).

A way of starting would be taking into account the process controls that have been briefy reviewed before. Transplant programs do have data on those parameters, some of them with associated occurrences or that have been shown in audits or in the risk assessment to be "diffcult" or "critical."

The parameters included in the outcome analysis are often used as indicators, for example, neutrophil above 500/μL at day X in ≥90% of transplants and/or graft failure in ≤5%. The accepted level or the accepted range has to be defned according to the center experience, the literature, etc. An individual delay in engraftment in a certain patient may be studied as an occurrence and a graft failure as an adverse event. But those are the studies on individual patients. But if those cases become more and more frequent in the transplant program, a detailed review of the system and a corrective action should be implemented. In these cases, the study should include not only clinical aspects (data of the patient, lines of chemotherapy, time to recover, conditioning, etc.) but also aspects of collection and processing, for example, number of cells and potential issues affecting viability. After reviewing the potential causes, an action should be taken and analyzed at a later step.

Regarding indicators of collection, a typical example would be collections fnished with the number of cells ≥X% or effciency of collection above a certain level in a percentage of procedures. Regarding the procedure itself, depending on the program, other useful indicators would be percentage of side effects, etc.

In processing, the indicators are focused on the product: products with positive culture below a certain percentage, viability over a certain percentage, etc.

The defnition of the indicator has to be clear: what are we going to measure and how [5]? The defnition, the range, etc., have to be included in quality documents. The way to obtain details to do the measure can be by reviewing the patient's clinical data or the collection or processing procedures, etc.

#### *Persons Responsible for the Measure and Timing*

Depending on the indicator and on the organization, indicators can be measured by a person directly related to the process (e.g., nurse of collection) or indirectly by the quality manager.

How often are indicators measured?

It depends on the point to measure and the urgency to take measures if the indicator deviates. They can be monitored monthly, quarterly, or, in some particular indicators, on a yearly basis.

#### *Indicator's Table*

After defning what and how to measure, by whom, and when, it can be useful to have a summary in a table (Table 12.1). This table would be flled with the results and the actions taken. And in a quick view, you can see the evolution of the measure within time.


**Table 12.1** Example of indicator's table

#### *T* **trimester**

The table may be split in clinical, collection, and processing if those units are independent. But results have to be shared with the entire program.

#### *Actions*

If the indicator falls above or below the target level, a corrective action shall be done. If an indicator is about to reach the level, a preventive action should be carried out in order to avoid reaching the dangerous level. For the development of corrective and preventive actions, see Chap. 11.

The action can be registered in the indicators panel (Table 12.1) or in the forms for occurrences. The deviation in the indicator, study of the cause, actions, etc., have to be opened and reviewed as other occurrences of the unit. The effectiveness of the actions has to be reviewed and will be seen in the following measures of the indicator.

#### *Other Indicators*

Besides the indicators seen, other key indicators may be required to monitor other aspects of the program. Indicators of the quality system itself may be required in other systems to review and keep under control particular points (e.g., corrective actions reviewed on time).

When selecting the process indicators, take into account that they have to be useful. It is not about having a long list, or indicators diffcult to measure, but they have to be a practical tool to measure and improve the quality system.

#### *Indicators Within Time*

Indicators are a dynamic tool. If one gets better and better results in the point of measurement, a more demanding objective can be set.

If occurrences start to happen in a certain part of the system, or if a new issue appears on the risk assessment, a new indicator can be opened to measure it more frequently and keep it under control.

In the same way, if a previously not-controlled issue gets to be fully compliant in each patient, year after year, having an indicator may not be as useful as before. It could be considered to be closed. If occurrences in that issue are seen again, it can be started again.

#### *Communication*

The measure of the indicators is a fundamental part of the quality management system. They have to be shared in the regular quality meetings.

They have to be included also in the annual review of the system [2]. To assess if an improvement is seen, a comparison with the indicators of the previous years is also advisable.

#### **References**


**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

# **Chapter 13 Writing a Quality Management Plan**

**Mara Magri**

## **Introduction**

Quality management systems (QMS) are central to FACT-JACIE accreditation standards [1]. As the frst edition of the JACIE standards has been published, every haematopoietic cell transplant (HCT) programme must decide on how to develop and implement its QM programme via a written quality management plan (QMP). The QMP should be "just right" for the type and size of an HCT programme. It should be a top-level overview of how the organization operates, aimed at implementing quality improvement whilst being realistic and deliverable. The QM plan (QMP) is usually collected in a single document, often and interchangeably referred to as the 'quality manual', that outlines how the QMS is implemented and managed.

Although JACIE standards require that the HCT programme has a QMP/quality manual, the style and structure are not specifed. There is considerable fexibility in how to prepare it, and an HCT programme can construct the QMP so that it is most useful and suited to the needs of the organization and ultimately patient care.

When writing a QMP, it is good practice to create a working group. The QMP needs to be tailored to the specifc needs of the HCT programme, so each facility should carefully consider how to best involve those who are needed. Also, the development of a comprehensive QMS is often the most challenging and time-consuming exercise that a clinical programme encounters when preparing for JACIE accreditation.

As HCT programs are almost always part of a broader healthcare organization, they can apply policies and procedures of the existing institutional QMS, for example, ISO certifed, or they can have a standalone QMS. An integrated HCT programme may, but is not required to, have one QMP that addresses all aspects of the

M. Magri (\*)

Hematology & BM Transplant Unit, ASST Papa Giovanni XXIII, Bergamo, Italy e-mail: mmagri@asst-pg23.it

clinical, collection, and processing facilities. If managed across organizational boundaries, there must be clear evidence of relationships among the QM programmes, usually associated with service-level agreements (SLA) detailing roles and responsibilities.

A generic, too broad, or poorly written QMP may be an indication that the QMS is not deemed an integral and important component of the HCT programme.

The key points to remember about the QMP are as follows:


## **QMP Structure**

The QM plan must detail all key elements that affect the quality of recipient and donor care and cellular therapy products as described in the FACT-JACIE standards and manual. The specifc SOPs to be followed for each of these elements does not have to be fully repeated in the QMP, but must be briefy summarized and referenced within the QMP and linked to the appropriate document where the details are described. Quality is the responsibility of all personnel involved in the HCT programme.

Although there is considerable fexibility in how to prepare a QMP, the content and structure should address the elements listed below.


If there are no organizational boundaries, it could follow the index of FACT-JACIE standards and manual, to be sure of having addressed all requested quality elements.

PLEASE NOTE: The basis for all audits and assessments of the QMS, including JACIE inspection, will be based on the contents of the QMP and the documents to which it refers.

#### *HCT Programme Description*

The QMP should begin with an introduction that contains an overview or description of HCT programme, its history, where it is located, how many beds/staff, basin of reference, type of procedures performed, i.e. autologous and/or allogeneic transplantation, paediatric and/or adult setting, clinical unit only, collection only, etc. It gives basic but important information about the HCT programme organization, interaction and activities; it is helpful for users and new staff and shows how changes occur over time. In case of an integrated HCT programme, the collection/processing profle would also be documented under this heading even if they have their own QMP.

#### *Organizational Structure – Roles and Responsibilities*

The QMP shall include or summarize and reference an *organizational chart of key positions and functions* within the HCT Programme, including clinical, collection and processing with a clear description of how key positions interact to implement the QMS in the HCT programme [2].

The overall organizational chart should include the titles of key positions and the reporting structure of the HCT programme. The chart should also outline the relationship among the different sections of the HCT programme (clinical, collection and processing at a minimum) even if supporting functions are performed by contract with other facilities or organizations. Lines of responsibility must be clearly defned in a way that is understood by all involved. It would be useful, but not mandatory, outlining the names of the key positions and verifying its applicability and correctness (Fig. 13.1).

Keeping clear and active communication within the HCT programme and between the HCT programme and any other departments and health care professionals is fundamental for the quality of processes performed.

**Fig. 13.1** The organizational chart of the "Colours" HCT programme

For example, JACIE standards require guidelines for communication with both the collection facility and the registry in the event of collection-related complications. Moreover, if responsibilities in donor selection, evaluation and management are shared, documented communication between teams is required.

It is clear then the HCT programme should address all these aspects in the QMP or in any other policy or procedure, detailing the methods of communication used such meetings, mails, reports and oral communication. The HCT programme should also describe when using one method instead of another. (i.e. written report for sharing of quality data among key individuals within participating facilities in the HCT programme).

#### *Key Personnel – Qualifcations, Training, and Competency*

The QMP should address policies and procedures (normally kept separate from the quality manual itself) summarizing personnel requirements for each key position in the HCT programme.

 These should include at least: a job description, initial qualifcations, new employee orientation, initial training, competency, and retraining when appropriate, continued competency assessed annually and continuing education.

All persons working in the HCT programme must have an accurate and clearly defned job description. Documentation of training for everyone must include all procedural skills routinely practiced. These requirements are detailed in FACT-JACIE standards and manual.

#### *Document Control*

The QMP shall include or summarize and reference a system for *document control* with the identifcation of the types of documents that are considered critical for the HCT programme and with the description of how they are controlled (Fig. 13.2). A critical document refers to a document that is directly related to and could impact patient care or cellular therapy product integrity.

The hierarchy and number of documents or extent of documentation is dependent on the processes, the size and the complexity of the HCT programme and will differ from one organization to another.

There are many different types of documents such as policies, SOPs, operative instructions, guidelines, protocols, providing description of activities and processes performed by the HCT programme. Other types of documents such as worksheets, checklists, records or forms are essential tools to provide quality control and evidence of conformity to FACT-JACIE standards (provision of evidence that what was planned has actually been done).

If the HCT programme participates in an existing QM programme in its Institution, it can or has to use portions of the hospital's QM programme, in


**Fig. 13.2** Document control table of the "Colours" HCT Programme

particular for the document control system. In this case, the quality manual can summarize and reference institutional policies or procedures for document control with due regard to any differences with FACT-JACIE standards (i.e. storage period of obsolete documents).

The system for document control should describe policies for the following:


The quality manual can summarize and reference institutional policies and procedures also for *agreements* preparation, outlining the roles and responsibilities of each party for the performance of critical tasks to maintain accreditations and to comply with applicable laws and JACIE standards. Agreements shall be dated, reviewed, revised on a regular basis as defned by the HCT programme, and at least every 2 years, and approved by both parties and by legal representative of the parties.

The term *agreements* includes the *contingency plans* with an external facility such as service-level agreements, contracts and preventive maintenance arrangements, and written agreements with donor registries and external laboratories performing testing of donors, recipients or cellular therapy products.

Moreover, the QMS shall ensure that essential services for patients are not interrupted. Each facility of the HCT programme – from collection to processing and administration of cellular therapy products – should have a continuity plan in place that details how services will be maintained if activities must temporarily be suspended or permanently ceased. Usually this plan will include a mutual agreement (a service-level agreement or contract) with another organization for the transfer of product, documentation and services in these circumstances.

For the emergency and disaster plan, the HCT programme may use institutional policies for the general responses; however, specifc SOPs and agreements with external facilities to address the safety of recipients and donors and of stored cellular therapy products are needed to augment the institutional policies.

An HCT programme within a single institution is not required to have written agreements for the collection and processing facilities.

#### *Key Performance Data and Outcome Analysis*

The quality manual shall include or summarize and reference policies and procedures for the collection and analysis of the selected *key performance indicators*  (from clinical, collection, and processing facilities) and their review by the Program Director at least once a year. *The outcome analysis of clinical data and the other quality measures, described in the paragraph "Tools for continuous quality improvement", are usually part of the annual report and they provide clues on areas for improvement and documented evidence of* the effectiveness of the QM Program (Fig. 13.3). All monitoring, measuring and evaluation outputs shall be documented, analysed and reported to staff and the HCT programme will choose how to aggregate data based upon its size and complexity.

The parameters to be monitored or reviewed in a regular fashion should be identifed in the quality manual and they should address all key elements of the HCT programme such as the safety and effcacy of the cellular therapy product, and the clinical outcome and adverse events related to the recipient, donor or product. These data shall be provided in a timely manner to facilities involved in HCT programme activities.

The HCT programme is also encouraged to defne internal benchmarks and compare them to national or international data.


**Fig. 13.3** Key performance data of HCT Programme "Colours"

Even the frequency for data collection and analysis should be established in the QMP. Some indicators may be reported with each occurrence, while others may be prospectively analysed and reported at defned intervals (i.e. during the QM meeting or the annual HCT programme review) to determine causes of issues and make improvement. There should be documentation of measurement results, analysis, improvement activities, and follow-up measurement.

FACT-JACIE standards state which data for each type of cellular therapy product and recipient type shall be evaluated. Some of them are as follows:


#### *Audits*

The QMP shall include or summarize and reference policies and procedures for planning and conducting *audits* of the HCT programme's activities to verify compliance with QM documents, applicable laws, or regulations, and JACIE standards.

If the HCT programme participates in an existing QMS in its institution, it can or has to use institutional policies or procedures for audit process. In this case, the quality manual can simply summarize the audit process and reference institutional procedures with due regard to any differences with JACIE standards (see "the compulsory audits" in FACT-JACIE standards and manual).

Alternatively, the audit process can be detailed in the QMP or in a dedicated procedure of the HCT programme describing the following:


# *The Management of Products with Positive Microbial Culture Results*

The QMP shall include or summarize and reference policies and procedures for the management of cellular therapy products with positive microbial culture results.

This quality element can be merged with the next one paragraph addressing problems and errors management or it can be treated in a dedicated procedure. In all cases, the QMP shall describe at a minimum the following aspects:


For each aspect, the HCT programme should detail what action is to be taken, who is responsible to take the action and the expected timeframe of the actions.

An over-arching document for the management of cellular therapy products with positive cultures is recommended because it could involve the clinical unit, the processing and/or the collection facility.

#### *The Management of Occurrences*

The QMP shall include or summarize and reference policies and procedures for *occurrences.* This term (which could be understood as non-conformity) refers to errors, accidents, deviations, adverse events, adverse reactions and complaints. As described in paragraph "Audits", if the HCT programme participates in an existing QM programme in its institution, it can or has to use institutional policies or procedures for the management of occurrences. In this case, the quality manual can simply summarize the process and reference institutional procedures with due regard to any differences with FACT-JACIE standards. Nevertheless, the HCT programme should defne errors, accidents, deviations, adverse events, adverse reactions and complaints and describe when, how, by whom and to whom each is reported. The HCT programme should defne when events need CAPA plans along with their plan to audit the effectiveness of the changes.

Alternatively, the management of occurrences can be detailed in the quality manual or in a dedicated procedure of the programme describing the following activities:


#### *Traceability*

Traceability describes the ability to verify the origin, location, or application of an item by means of documented recorded identifcation.

In JACIE standards, *traceability* means the ability to locate and identify the cellular therapy product, the donor and the recipient during any step from procurement, through processing, testing and storage, to distribution for transplant to the recipient


**Fig. 13.4** Traceability of unrelated haematopoietic progenitor cells donor and recipient data

or disposal. Traceability also applies to the facilities and personnel involved in the above mentioned activities so it implies the ability to identify the collection facility, the tissue establishment and the Clinical Unit in each step of the process (Fig. 13.4). [3].

Given the premises, the quality manual shall include or summarize and reference policies and procedures for cellular therapy product tracking and tracing that allow full traceability of donations from donor to recipient, all materials, reagents and equipment that come into contact with cellular therapy products and tracing from the recipient or fnal disposition to the donor.

A policy for the traceability of all patients and their clinical and medications data (including blood transfusions) is also mandatory to guarantee patient safety.

If the HCT programme participates in an existing QMS in its institution, it can or has to use institutional policies or procedures for traceability (i.e. medical records management, inventory management, drug prescription and administration). In this case, the quality manual can simply summarize the process and reference institutional procedures with due regard to any differences with FACT-JACIE standards.

#### *Business Continuity Policy*

The HCT programme should be prepared for situations that may interrupt operations so that such interruptions do not adversely affect recipients, donors, or cellular therapy products. While a policy or procedure is required that addresses emergencies and disasters as describe before (see paragraph "Document control"), the HCT programme must also have a plan for the management of temporary interruptions (actions to take, who needs to be contacted, how to prioritize cases, key personnel to be involved and notifcation of staff).

The QMP shall include or summarize and reference policies and procedures for actions to take in the event the *HCT programme's operations are interrupted*.

For computerized systems of critical processes (e.g. electronic health record, computerized drug prescription), provision (e.g. business contingency plan) should be made to ensure continuity of support for those processes in the event of a system breakdown (e.g. a manual or alternative system).

Generally, the institutional information technology department ensures that softwares in use are validated for their function and that there is a regular schedule of back-up to allow for retrieval of information when necessary. In this case the quality manual can simply summarize the process and reference institutional procedures with due regard to any differences with FACT-JACIE standards.

#### *Qualifcation and Validation*

#### **General Principles**

*Validation* is the part of the QMP concerned with proving that all critical aspects of the HCT programme operations are suffciently under control to provide continual assurance that product/service will remain safe for patients and ft for purpose.

Validation is usually split into two components: qualifcation and process or testmethod validation.

The term *qualifcation* is applied to each part of the process including facilities, equipment, computer systems, materials and operators. Each item should be qualifed separately to demonstrate consistent performance. Process validation should only be performed once all the items used have been qualifed.

The quality manual shall include or summarize and reference policies and procedures for *qualifcation* and for *validation or verifcation* of critical procedures.

Sometimes a procedure regarding qualifcation and validation called validation master plan (VMP) could be in place for the processing facility. In this case, the QMP can simply summarize the processes and reference this VMP, applying it even to bone marrow and peripheral blood collection facilities.

Alternatively, the qualifcation and validation process can be detailed in the QMP or in a dedicated procedure of the HCT describing the following:


#### *Quality Risk Management*

Evaluation of risk is a process to assess and document the risks involved in a change in a process, procedure or environment that has the potential to affect a critical procedure (patient care safety, product integrity, sterility, viability and/or recovery).

The QMP shall include or summarize and reference policies and procedures for the *evaluation of risk* before introducing a new activity and changes to a process to confrm that the changes do not create an adverse impact or inherent risk elsewhere in the operation. Risk assessment is not a once-only process but a cyclical one (Fig. 13.5) considering a continuous re-evaluation of residual risk.

Since the risk assessment represents a basic step to go through in the validation process and it is one of the key elements also for ISO standards, the HCT programme could have a dedicated procedure for it. In this case, the quality manual can simply summarize the processes and reference to the existing document.

Alternatively, the risk assessment process can be detailed in the QMP or in a dedicated procedure of the HCT programme describing the following elements:

• Approach to risk assessment used (i.e. brainstorming, Hazard Analysis and Critical Control Points (HACCP), Failure Mode and Effects Analysis (FMEA) and Failure Mode, Effects and Criticality Analysis (FMECA)).

**Fig. 13.5** Cycle of risk assessment of HCT programme "Colours"


#### *Obtaining Feedback*

The quality manual shall include or summarize and reference policies and procedures for *obtaining feedback* from associated collection and processing facilities and from donors and recipients or legally authorized representatives. It may be obtained directly by the HCT programme; however, it is also acceptable to use a hospital-wide system, such as patient satisfaction surveys.

#### *Tools for Continuous Quality Improvement*

Products, services or processes of the HCT programme should be constantly evaluated and improved for effciencies, effectiveness and compliance (Fig. 13.6). If the HCT programme participates in an existing QMS in its institution, it can or has to use institutional policies or procedures for continuous quality improvement system. In this case, the QMP can simply summarize the process and reference institutional procedures with due regard to any differences with JACIE standards. Alternatively, the continuous quality improvement system can be detailed in the QMP or in a dedicated procedure of the HCT programme describing the structured planning approach to evaluate the current practice processes and improve systems and processes to achieve the desired outcome.

Input to management reviews shall include at a minimum the following:


**Fig. 13.6** Continuous quality improvement process of the "Colours" HCT programme


As described in the paragraph "Key performance data & outcome analysis", the QMP should describe the frequency for data collection and analysis. The representative in key positions involved in the quality management review should be defned, as well as the means of communication to the HCT programme staff of Key performance data and review fndings (at a minimum on an annual basis), and the type of documented information to be retained (i.e. the minutes and attendance lists).

#### *Other Aspects*

The QMP can also provide information on other key elements of the quality management system of the HCT programme such as the following:


If the HCT programme participates in an existing QMP in its institution, it can or may even have to use institutional policies or procedures. In this case, the QMP can simply summarize the abovementioned elements and reference institutional procedures with due regard to any differences with FACT-JACIE standards. Alternatively, some aspects like operational environment equipment and supply management can be detailed in the QMP or in dedicated procedures of the HCT programme.

Typically, the QMP of the processing facility might include a map of the laboratory premises, showing all space that the laboratory uses and restricted points of access. The reagent section might address order procedures, storage requirements, preparation and quality control of reagents.

Also, requirements for instrument/equipment management should be addressed in the QMP or in dedicated procedures of the HCT programme, including the following:


#### **References**


**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

# **Chapter 14 The Accreditation Process**

**Mara Magri and Raquel Espada Martín**

The complexity of haematopoietic cell transplantation (HCT) as a medical technology and the frequent need for close interaction and interdependence between different services, teams and external providers (donor registries, typing laboratories, etc.) distinguish it from many other medical felds [3]. At around the turn of the millennium, recognition of these challenges led to efforts by the HCT community to standardize processes based on consensus to better manage quality, including the inherent risks of HCT [2]. Ever since, HCT has continued to be a pioneer in setting agreed clinical quality standards [5, 8] and subsequent external inspection and certifcation via the process of accreditation (via JACIE). An accredited programme can therefore demonstrate that it is performing at a required level of practice in accordance with agreed standards of excellence, including operating an effective quality management system (QMS). Such a hallmark of quality provides reassurance to healthcare professionals, health service payers and, most importantly, patients and their families.

The accreditation process is divided into three phases. The frst phase is a preinspection phase where the applicant submits the relevant documentation and the inspectors review it in advance of the inspection. The second phase is an inspection phase, where the inspectors assess on-site if the documentation from the preinspection phase meets the reality of the day-to-day work in the centre through interviews with key personnel, tour of the facilities and review of additional documentation. Inspectors document fndings and observations in the inspection report which is reviewed by the accreditation committee which decides on the next steps

M. Magri

R. E. Martín (\*) JACIE Accreditation Offce, EBMT, Barcelona, Spain e-mail: raquel.espada@ebmt.org

© The Author(s) 2021 123

M. Aljurf et al. (eds.), *Quality Management and Accreditation in Hematopoietic Stem Cell Transplantation and Cellular Therapy*, https://doi.org/10.1007/978-3-030-64492-5\_14

Hematology & BM Transplant Unit, ASST Papa Giovanni XXIII, Bergamo, Italy e-mail: mmagri@asst-pg23.it

for the centre to achieve the accreditation. The third phase is a post-inspection phase, where the applicant submits evidence of corrections for the defciencies identifed in the report. The programme achieves compliance once the inspectors assess the evidence of corrections, the standards are compliant and the accreditation committee gives the approval. After achieving the accreditation, the main challenge for the programme is to maintain all the aspects, including the QMS, making it more robust and adhering to the new editions of the FACT-JACIE standards and manual.

#### **Why Seek Accreditation?**

Accreditation is the means by which a centre can demonstrate that it is performing a required level of practice in accordance with agreed standards of excellence and certify that it operates an effective QMS.

A quality management system is a mechanism to ensure that procedures are being carried out in line with agreed standards with full participation by all staff members. In an HCT programme, this ensures that the clinical, collection and laboratory units are all working together to archive excellent communication, effective common work practices and reassurance for patients. It is a means of rapidly identifying errors or accidents and resolving them so that the possibility of repetition of the problem is minimized. It assists in training and clearly identifes the roles and the responsibilities of all the staff.

Once the required level of quality has been achieved through modifcations to practice, the remaining challenge is to maintain this standard of practice. With a working quality management system in place and adequate resources, the fundamental elements necessary to sustain the programme are continued staff commitment and vigilance.

Initial evidence of a positive relationship between the implementation of a QMS and an outcome of HCT in Europe was published in 2011 [6]. In this paper, patients' outcomes were systematically better when the HCT centre was at a more advanced phase of JACIE accreditation and independent of year of transplantation and other risk factors. Another analysis [7] was performed on a large cohort of patients who received either an allogeneic or an autologous HCT between 1996 and 2006 and reported to the EBMT database. The authors showed that the decrease of overall mortality in allogeneic HCT procedures over the 14-year observation period was signifcantly faster in JACIE-accredited centres, thus resulting in a higher relapsefree survival and overall survival at 72 months from transplant. Such improvement was not shown in autologous transplantation. Similar results published in an American study [10] showed that centres accredited by both FACT and Clinical Trial Network (CTN) demonstrated signifcantly better results for more complex HSCT such as HLA-mismatched transplants. These data reinforce the concept that clinical improvement is driven by the implementation of a quality management system embedded in external accreditation standards, especially in the context of more complex procedures. This process also results in a wider standardization of procedures across different countries and geographic areas, thereby contributing to providing patients with similar treatment expectations even when accessing different health management systems. A comprehensive review summarized these developments [13]. Other studies have assessed the impact of accreditation on quality and organizational aspects of transplantation programmes [1, 4, 11].

## **Where to Start?**

Before starting with accreditation process, the HCT programme needs to be formally recognized by the institutional authorities and by competent authorities if needed. This is an important step to be entitled to assign duties and responsibilities to the key persons of the HCT programme.

The accreditation process starts with a centre's aspiration to achieve certifcation and subsequent plan (see Fig. 14.1).

**Planning** The frst step is preparing a timetable (see Table 14.1) triggered on the goal to reach JACIE accreditation. The introduction of JACIE standards is embedded in an accompanying quality management system, the type of which is at the discretion of the single HCT programme [14].

**Implementation of an action plan and its monitoring** The second step is the preparation of an action plan detailing all the operative activities, their timeframe, the key persons, and responsibilities involved and the fnal objectives to be reached. Where there is a QMS already implemented by the hosting institution, the preparation of the plan of action for achieving accreditation should be organized in close collaboration with the quality offce of the institution.

**Fig. 14.1** Aspects to consider prior to starting the accreditation process


**Table 14.1** Timetable

The analysis of the HCT programme processes and activities and the organization of the QMS documentation already available are the starting points to prepare a good action plan. The analytical comparison between the documentation already present and requirements of the FACT-JACIE standards enables evaluation of how much commitment must be expected in terms of personnel and working time to complete the preparation of documentation required by FACT-JACIE standards.

The action plan must also include education on FACT-JACIE standards of HCT programme staff, possibly before starting with document preparation, to enable personnel to work on documentation and on the accreditation process (awareness and competence).

The action plan must be monitored during its application so that it can be corrected and amended if necessary (action plan adjustments). The monitoring can be carried out through regular and routine meetings of people responsible of the different working groups and/or through focussed audits (on quality system documentation or on processes).

#### **Phases of the Accreditation Process**

Accreditation is the means by which a centre can demonstrate that it is performing a required level of practice in accordance with agreed standards of excellence and certify that it operates an effective QMS. According to the International Society for Quality in Healthcare, accreditation is a process "in which trained external peer reviewers evaluate a health care organization's compliance with pre-established performance standards ... Unlike licensure, accreditation focuses on continuous improvement strategies and achievement of optimal quality standards, rather than adherence to minimal standards intended to assure public safety" [12].

Programmes interested in achieving accreditation for hematopoietic cellular therapy product collection, processing and administration can contact relevant accreditation organizations, including the following:


Although each accreditation organization has its own accreditation process and specifcations, the following sections provide a general description of the different phases that the applicants are subject to. The accreditation process is divided into three main phases: pre-inspection, inspection and post-inspection.

#### *Pre-inspection Phase*

HCT programmes seeking accreditation are encouraged to start the accreditation process with the accreditation organization of their choice once their QMS has been in place at least for a year and there is suffcient evidence to prove compliance with the FACT-JACIE standards.

Out of the three phases of the accreditation process, the pre-inspection phase is a phase that often requires more efforts for all the involved parties: applicant and inspectors. The pre-inspection process starts when applicant submits the corresponding documentation to the accreditation organization for review and approval.

Following are the documents that are to be provided during the preinspection phase.

#### **Application Form**

Key information about the HCT programme seeking accreditation should be provided, including the following:


The information provided by the HCT programme in the application form enables the accreditation organization to determine the eligibility for the accreditation process.

#### **Self-Assessment Standards Checklist**

Applicants need to self-assess their compliance with every one of the standards indicating if they comply or not with it and referencing supporting documentation as a proof of compliance. The information provided by the programme in the selfassessment checklist enables the applicant, the accreditation organization and the inspectors to determine the readiness of the centre for the accreditation process.

Once the application form and self-assessment checklist are reviewed and approved by the accreditation organization, the applicant provides an established set of pre-inspection documents.

#### **Pre-inspection Documentation**

This consists of selection of documents that the applicant needs to submit prior to the on-site inspection. This documentation allows the inspectors to understand the centre's activity, organization and to check compliance with some of the standards before the on-site visit. Depending on the accreditation organization (and subject to the language capabilities of the inspectors), the documentation can be submitted in

the language of the centre or only in English. Following are examples of the key documentation requested:


Examples of pre-audit documentation can be found at https://www.ebmt.org/ jacie-document-quicklist.

Support prior to submitting the forms is available from the accreditation organization, i.e. the JACIE offce. Once the application is submitted to the accreditation organization, each HCT programme is assigned to an accreditation coordinator to help and guide through the process. Also, the accreditation organizations have supporting guides to accompany centres during the process.

Completing the application form, self-assessment checklist and pre-audit documentation thoroughly and accurately leads to a more effcient on-site inspection.

During the pre-inspection phase, applicants will be requested to sign an accreditation agreement with the accreditation organization and will be invoiced with the corresponding accreditation fees.

Once all the pre-inspection information is submitted, the accreditation organization starts to assemble the inspection team for the on-site inspection. Each accreditation organization has their own pool of inspectors who are volunteers and experts in one or more of the areas covered by the FACT-JACIE standards. Inspection teams consist of at least one inspector per area to be inspected: clinical, collection and processing, one of whom is also a team leader. For example, if the applicant applies for adult clinical, collection (bone marrow and apheresis) and processing accreditation, the inspection team will consist of the following: a clinical inspector, an apheresis inspector and a processing inspector. Each inspector is responsible for assessing the standards under their area of expertise and it is the clinical inspector who is usually responsible for the marrow collection facilities. Some accreditation organizations also include a quality manager specialized inspector. When a quality manager inspector is included, they are responsible for assessing the QMS in relation to the quality-related standards in the HCT programme. During this process, both applicant and inspectors need to communicate to the accreditation organization any confict of interest to exclude those inspectors from the inspection team. Furthermore, one of the inspectors also has the additional role of being the team leader. The responsibilities of the team leader include to provide a general overview of the interactions between the units of the programme and to become the main point of contact (among the inspectors, with the applicant and with the accreditation organization).

As soon as the inspection team is confrmed:


#### *Inspection Phase*

The inspection phase is the most visible part of the accreditation process. Inspectors will travel to the HCT programme to verify that the information provided during the pre-inspection phase corresponds to the way they work and that it meets the requirements of the FACT-JACIE standards. The inspection is a thorough peer-reviewed examination of the aspects of the HCT programme and/or its component parts.

Inspections are conducted in the language of the centre or in English depending on the accreditation organization.

The on-site inspection consists of 1 or 2 days of inspection and comprises the following items:


inspection team and the programme director will discuss any sensitive issues identifed. Afterwards, the inspection team meets with all the personnel involved in the on-site inspection to explain the main fndings and observations from each of the units inspected. The team leader takes the opportunity to explain the next steps in the process and highlights that inspectors write the report based on their observations, but it is the accreditation committee that makes a judgement on the compliance of the centre with the standards. This closing meeting helps applicants to manage the expectations about the inspection report.

After the on-site inspection, inspectors write the inspection report (see Fig. 14.2) identifying which standards are compliant and which ones need further adjustments. The inspection report is provided by the inspectors to the accreditation organization for review and it is presented to the accreditation committee (see Fig. 17.5) to decide the next steps for the HCT programme to achieve the accreditation. Once the report is fnalized with the observations from the inspectors and the committee, it is provided to the applicant so that they can continue working towards achieving the certifcation for accreditation. The report is a fundamental part of the accreditation process.

The possible results of the accreditation report are as follows:


**Fig. 14.2** Report pathway

#### *Post-inspection Phase*

Once the applicant receives the inspection report, they can start working correcting the defciencies, implementing the corrective actions, and generating the supporting evidence. The degree of defciencies identifed will vary in seriousness. In most cases, it will be suffcient to provide documentary-based evidence, while in other cases, for example when the QMS is immature or facility structures are not adequate, a focussed reinspection will be necessary. Whether the centre submits documentary evidences or is subject to a focussed inspection, the same inspection team that participated in the inspection phase will assess the adequacy of the corrections. When those are assessed as compliant by the inspectors and are approved by the accreditation committee, the applicant is awarded with accreditation.

Some accreditation organizations are assessing how to offer a stepwise accreditation programme for programmes in low-to-middle income countries (LMICs). The main concept is to help centres to achieve full accreditation in different stages, which makes the accreditation goal more reachable. Programmes subject to the stepwise process must achieve the same level of compliance as programmes going through the full accreditation process, but they can do it more gradually over a longer period. This stepwise programme would allow LMIC to connect with an international network focussed on quality in HSCT and could also serve to stimulate local authorities to support accreditation in the interest of patients and donors.

#### **Plan the Post-accreditation Period**

Maintaining JACIE accreditation is probably as challenging as being awarded it frst time. JACIE standards are not something that should be forgotten about until getting ready for the next accreditation cycle. The effort in the post-accreditation period is to maintain an up-to-date QMS, making the FACT-JACIE standards a part of the everyday life of the HCT programme.

Any system, without maintenance, is destined to deteriorate, including adherence to key aspects such as the QMS that depend on the possibility of changes in many aspects in the internal institutional and external health care systems. The continuous improvement of the QMS is not a simple update of the documented information over time but also means maintaining all elements and ensuring implementation on everyday working practices.


Prompt and accurate *collection of occurrences* (this term refers to errors, accidents, deviations, adverse events, adverse reactions and complaints deviations) should be maintained and the need for CAPA plan should be investigated.

If you do not continue to develop and maintain JACIE, most of the hard work in achieving accreditation will become redundant and you will fnd yourself back at the beginning when applying for reaccreditation.

# **Key Agents**

This peer-reviewed accreditation process is possible, thanks to volunteer professionals in the feld of HSCT, who devote their valuable time and expertise to contribute, promote and implement quality in the transplant community: inspectors, accreditation committee members and cellular therapy standards committee.

#### **Inspectors**

Inspectors are involved in the three phases of the accreditation process (see Fig. 14.3); thus, they dedicate their efforts and knowledge to learn about the applicant and visit their programme to assess their compliance with the standards. As

**Fig. 14.3** Accreditation process fow, documentation and key agents

previously mentioned, they are the eyes and ears of the accreditation committee and include all their fndings in the inspection report. Inspectors are also involved in the review of the evidence of corrections during the post-inspection process, and thus they follow the progress of the programme from the application until they achieve certifcation of accreditation.

The entire process is usually performed in a collegial and positive atmosphere and is often a learning and rewarding experience for both inspectors and applicants. In addition, inspectors beneft from meeting and collaborating with colleagues while helping to implement and promote quality in the transplant community [9]. Accreditation organizations might offer specifc benefts to their volunteer inspectors, such as discount in the application fees of the inspector's centre or educational events.

Professionals from HCT feld interested in becoming inspectors should contact the accreditation organization to learn more about the requirements. Inspector requirements are based on professional experience, completion of an inspector training course and associated exam. Before becoming an inspector, candidates must participate in the observation of an inspection.

#### **Accreditation Committee Members**

Accreditation committee members are the main source of expert opinion and peer review. Membership is formed by experienced inspectors from all the areas, clinical, collection and processing, and some accreditation organizations also include quality managers members. The accreditation committee members meet regularly to discuss the inspection reports, determine the next steps for the centres to achieve compliance and decide on the accreditation of the centres.

#### **Cellular Therapy Standards Committee Members**

Members of the cellular therapy standards committee oversee establishing, maintaining and reviewing the standards. Members are usually experienced inspectors and members of the accreditation committee.

Standards are reviewed periodically and are subject to a public consultation process before the publication of the fnal version.

#### **References**


**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

# **Chapter 15 Data Management**

**Fazal Hussain, Riad El Fakih, and Mahmoud Aljurf**

# **Data Management**

Hematopoietic stem cell transplantation (HSCT) is a multidisciplinary and defnitive treatment modality for myriads of life-threatening conditions. HSCT has witnessed tremendous development and evolution since its inception and has emerged as an area of high priority. Traditionally, HSCT has been used and continues to expand as a defnitive treatment for multitudes of malignancies, inherited disorders, and bone marrow failures [1–3]. This growth has been witnessed not only in the developed countries but also in low- and middle-income countries (L&MIC). Cellular therapies have emerged as the most promising treatment modalities in HCT, and this trend is expected to continue.

HSCT databases are the backbone of any quality transplant program to achieve desired end states as per the institutional lines of efforts. These registries are organized systems to collate uniform data using observational study methodology to determine trends, patterns, and treatment outcomes in HSCT. The source documents for these outcome registries are mostly the patient's medical record. Transplant database encompassing complete, accurate, and reliable transplant data is geared toward capturing evolving trends, best practices, and resource allocation/utilization and streamlining multidimensional quality indicators for continuous quality improvement (CQI) and optimal outcomes. Data management is crucial for determining trends, developing quality observational studies, and answering the

F. Hussain (\*)

College of Medicine, Alfaisal University, Riyadh, Saudi Arabia e-mail: fhussain@alfaisal.edu

R. El Fakih · M. Aljurf Oncology Center, King Faisal Specialist Hospital & Research Centre, Riyadh, Kingdom of Saudi Arabia e-mail: relfakih1@kfshrc.edu.sa; maljurf@kfshrc.edu.sa

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questions that can't be answered otherwise to improve HSCT knowledge globally. Observational registries provide state of current knowledge and gaps in evidence to form the basis for prevention/intervention programs, delivery, and effectiveness. They can help in designing the optimal schema for prospective and retrospective studies and for comparative analyses of diverse HSCT strategies for HSCT vs. non-HSCT therapies. Registries are particularly useful in situations where a comprehensive and fexible research design is needed or when the purpose is to discover how a product works in a wide variety of sub-groups, including ethnicity and socioeconomic status. A hybrid approach registry collects data retrospectively and prospectively. If data collection is suffciently comprehensive, outcomes fndings from patient registries can be widely generalizable. Rapidly evolving HSCT technology and widely varied outcomes among diverse patient populations need to be balanced with data management support.

Transplant databases are aimed at monitoring the natural history of the disease, demographics, therapeutic interventions, toxicity/safety, treatment effectiveness, quality assessment, and sustainability of this high-stake tertiary care service in a systematic approach. Short- and long-term complications of HSCT require longterm follow-up of patients. Databases and the consent formats need to be approved by the Institutional Review Boards (IRBs) as per the local rules and regulations and the Standard Operating Procedures (SOPs). Data managers (DMs) play a signifcant role in capturing contemporary knowledge about the indications, stem cell utilization, benchmarking data quality, and assessing outcomes for better resource planning/allocation/utilization [4]. Minimal essential data on each transplant recipient and donor can be captured using EBMT and CIBMTR minimum essential forms (MED-A), and Transplant Registry Unifed Management Program (TRUMP) by the APBMT, the survey form of the EMBMT, and other organizations. The HSCT database is pivotal in conducting innovative observational registry studies, providing a platform for clinical trials, and enhancing transplant outcomes. Qualifed, trained, and experienced personnel are essential to initiate and maintain such registries [5]. Data managers are required for quality data management and their continuing education and training, and interdisciplinary teamwork is critical for the optimum use and outcomes of the HSCT databases [6]. Precision, communication, collaboration, and close coordination are crucial for achieving the desired end states. High-quality transplant program data management encompasses advanced methodology, operational excellence, enhanced validity, and discernable outcomes (Table 15.1). Changing trends and patterns in personalized medicine have underscored the importance of data management to ensure that all cellular products are being processed as per protocol, safety standards, and guidelines to optimize disease outcomes. Data management is a dynamic process with myriads of dimensions, applications, and deliverables as the backbone of quality HSCT program, leading to evidence-based medicine. If designed and executed correctly, it can yield huge dividends to fll in the knowledge gaps and support the center's lines of effort (Table 15.2).

Data management is pivotal for a high-quality HSCT program to identify challenges, fnd solutions, and overcome potential barriers to maximize clinical and patient-reported outcome measurements (PROMs). Following guidelines and


(continued)

#### *Data utilization and publications* Overlapping registries/databases Integration/interfacing/interoperability Access to data Authorship guidelines *Funding* Sustainable funding sources for long-term follow-up Quality data generates new funding sources **Table 15.1** (continued)

Courtesy of Hussain et al. [11]


Courtesy of Hussain et al. [11]

recommendations from the CIBMTR, EBMT, WMDA, and Worldwide Network of Blood and Marrow Transplantation could be an effective way of streamlining data management issues for the HCT programs. However, following the data standards set forth by the HSCT accreditation bodies in the USA (Foundation for Accreditation of Cellular Therapy [FACT]) [7]and in Europe (Joint Accreditation Committee of the International Society for Cellular Therapy and the European Group for Blood and Marrow Transplantation [JACIE]) [8] is the ideal way to promote improvement in data quality of the HSCT program from harvesting to grafting. Regional transplant registries can promote HSCT in a specifc region and identify locoregional trends and practices, standards and interventions, and benchmarking outcomes. National registries can be used to benchmark transplant outcomes using the large multinational outcomes registry (EBMT, CIBMTR, EMBMT, APBMT, etc). As a reference. CIBMTR carries out an annual assessment of one-year survival postallogeneic HSCTs in each transplant center in the USA and provides it to participating centers and the public. The globalization of patient and donor registration for HSCT is a realistic goal and can contribute to the improvement of patient care, outcomes, and donor safety. Registry data have provided valuable insights into international differences in indications for HSCT and access to HSCT. Accuracy, reliability, and validity in data management are pivotal for quality improvement, the effciency of care, and donor/recipient outcomes. Therapeutic outcomes of HSCT are optimized by utilizing myriads of clinical indicators encompassing transparency, close coordination, teamwork, and effective communication in a multidisciplinary approach (Table 15.3). Studies have shown a signifcant improvement in the donor and recipient care in the accredited centers by adhering to international

**Table 15.3** Strengths of HSCT databases


Provide meaningful data for decision-making where a clinical trial is not feasible or practical Approximation of treatment impacts is more realistic

Courtesy of Hussain et al. [11]

standards for optimal clinical, laboratory, and auxiliary practices in HSCT [9]. The databases' value is enhanced by following the universally acceptable ethical and quality standards for the design, collection, analysis, reporting, monitoring, and auditing of the data. Scientifc rigor and transparency of the registry can be strengthened by following good registry practices. Easy access of registry data to the investigators and ensuring safeguards for credible, accurate, and reliable data are cardinal elements of a quality registry. Registries must provide assurance for the privacy, confdentiality, and integrity of data.

Quality management is crucial in the operational domain of a high-quality HSCT program for optimizing patient outcomes as per the existing SOPs and playbooks for effcient, quality, and sound therapeutic yields. The minimum essential elements of data management are as follows:

**SOPs/IPPS/Playbook** SOPs and control measures for HSCT data management ensure the integrity, confdentiality, and authenticity of transplant data. Documentation is crucial in setting up and maintaining a quality HSCT program as per the written SOPs or Internal policy and procedures (IPPs) to ensure that each team member is aware of its roles and responsibilities at the operational, strategic, and tactical levels. The playbook is pivotal for the continuity of quality data management by underscoring techniques, tactics, and procedure of data collection, quality assurance and outcomes to optimize operations planning and execution. It highlights the importance of what, when, where, who, why, and how to optimize the process fow in a multidisciplinary approach. The playbook provides a standardized and centralized guidance to conduct HSCT data management, record data into the appropriate data management system repository, and utilize the existing outputs to analyze, plan, and forecast future requirements and best practices. It also provides instructions for accessing the data management systems and generating reports and specifc instructions for data capture support.

**Trained/Qualifed Personnel** Qualifed and trained personnel with adequate HSCT experience and process knowledge are pivotal to design, conduct, and manage the registries (processing, multidisciplinary coordination, and managing regulatory issues). Collaborative efforts of DMs can help facilitate registry activities from data acquisition to data processing and publications. The data management staff are responsible for the smooth fow of pre-transplant, transplant, and post-transplant care, documentation, validation, discrepancy management, adverse events reporting, and safety as per the local and international standards.

**Data Processing** The scope and quality of the data collected determine the value of an outcome registry. It's critical throughout the entire life cycle of HSCT by assessing donor/recipient eligibility, screening, workup, informed consent process, HLA matching, follow-up, protocol-specifc procedure, data entry, regulatory compliance, pharmacy coordination, quality assurance, risk communication, document submission, and data management of transplant patients per treatment protocols. The purpose and objectives outline the scope of the outcome registry and are affected by a myriad of factors. Size of the registry, complexity of the data elements and outcomes collected, number of observations, and duration are essential considerations to achieve registry objectives. A core dataset of crucial variables and patient outcomes are defned by the registry to accomplish its objectives. An internationally accepted core dataset has been developed by the major outcome registries (CIBMTR, EBMT) and is recognized internationally as a model for HSCT registries endorsed by the WBMT. Case report forms (CRFs) need to be revised periodically to ensure capturing of most current data (novel biomarkers, interventions, etc.). The reliability, accuracy, and validity of data are critical elements of a quality outcome database. Data comparability is crucial for interpretation and depends on the standardization of methodology and the diagnostic criteria utilized. Robust quality control can be achieved by regular internal and external audits, monitoring, and evaluation. Good quality, user friendly, cost-effective, reliable, validated, and compatible health information systems are essential for maintaining good quality outcome databases and registries [10]. Next-generation and web-based data entry applications, with effcient data validation tools, are required to streamline observational databases. Enhanced electronic data capturing efforts with built-in auditing and quality assurance tools can be very helpful in performance improvement, research, and publications.

**Cultural Sensitivities/Communication** There is signifcant cultural, social, and economic heterogeneity globally. Such cultural sensitivities and language barriers among diverse countries in a regional/international database/trial need to be addressed. Cultural sensitivities must be considered when collecting patientreported information, like quality of life (QOL) data. Sometimes, certain QOL tools cannot be used for sociocultural reasons. Therefore, QOL forms should be culturally sensitive and validated.

**Regulatory Compliance** This is pivotal for yielding high-quality outcomes of transplant data and is monitored by internal and external regulatory authorities (IRB, Sponsor, FDA, etc.). Safeguarding patient safety, privacy, and confdentiality, with dignity and respect, while on research protocol is paramount. Developing and implementing SOPs/IPPs, administrative and regulatory support, surveillance, and monitoring are critical quality indicators of the participant's privacy and confdentiality protection during collection, storage, and utilization of data. Supporting internal and external quality assurance site visits/audits, clinical review committees, Data and Safety Monitoring Boards (DSMB), morbidity and mortality (M & M) meetings, and QA committees are required elements of a quality data management program. Outcome registries and databases are often considered "low risk" in terms of the potential of harm to human subjects for being observational. Privacy concerns with regard to identifable patient information can be addressed by registries by collection of de-identifed data and collection of identifable data for "internal use" with linked identifers. A signifcant proportion of the annual HSCT performed globally use allogeneic donors acquired through a donor registry or a cord blood bank. Since most of the donor registries and cord blood banks are required to report outcomes of products used for transplants, patient outcomes can be linked with the donor products with justifcation for identifable information gathering. WHO has recommended that data collection and data analysis should be considered a mandatory part of transplantation programs following full ethical, legal, and privacy guidelines.

**Pharmacovigilance** Adverse drug reaction reporting, risk management, and patient safety are paramount for a transplant program and are managed by continuous surveillance, effective communication, and robust teamwork. During transplant, patient safety monitoring is a critical component throughout the transplant by precise coordination and communication among all the stakeholders.

**Intellectual Property Rights, Data Utilization, and Publications** Integration, interoperability, full access to each center's own data, and clearly defned authorship guidelines (based upon the number of transplants, contribution, and the center participation, etc.) are the pivotal success elements. Transplant data can be used to plan prospective HSCT trials in areas not well studied (role of geographical variations, genetic pre-disposition, genotypic and phenotypic variations, and biology of disease) by utilizing preliminary registry data. It can also be utilized to estimate outcomes and accrual patterns, sample size calculations, and implementation plans. Information about the most commonly used supportive care measures can be used to adapt protocols to standard practices and, thus, increase their acceptability in the transplant community. Comparison of clinical trial outcomes with observational outcomes can give an insight about generalizability and patient selection practices. The source of stem cells is highly infuenced by chance for each patient, and in many occasions, it will not be possible to apply prospective randomization to answer some of the important clinical questions.

**Funding and sustainability** Collection of complete, accurate, and high-quality data is resource-intense and spans over a long period. To be sustainable over the protracted time frame, long-term fnancial support is required. Consideration of the intended uses of the transplant database and those sponsors who can derive value from registry information (government/non-governmental agencies, scientifc organizations, research collaborators, biopharmaceuticals, accreditation bodies, philanthropic organizations, etc.) could provide additional funding support. In the context of the contract for the US Stem Cell Therapeutic Outcomes Database, the CIBMTR derives substantial funding from the Department of Health and Human Services to support its outcomes registry operations. As an outcomes registry develops robust information, it can be a rich source of data for research, and grant funding to support research represents an excellent opportunity. Biopharmaceuticals or device manufacturers may have an interest in registry data to better understand utilization of their products, and short-term projects or long-term reporting may represent a funding source. Outcome databases should remain vigilant for the innovative and collaborative research opportunities to utilize or expand the database to secure new funding opportunities.

**Quality Assurance and CQI** These concepts are fundamental for generating highquality, accurate, and reliable outcomes. Quality Assurance (QA) is the best way to determine process deviations and non-compliance. Quality transplant data has minimal unknowns or missing variables and acceptable levels of procedural deviations per regulatory requirements specifed for transplant program. Periodic QA site visits and audits conducted by the regulatory authorities and accreditation bodies ensure compliance, safety, and optimal outcomes. The accreditation bodies for HSCT in the USA and Europe (FACT, JACIE, etc.) mandate that transplant centers collect and utilize standard core dataset defned by the feld to analyze and understand their program quality. The built-in internal and external audit process for continuous quality improvement (QQI) is one of the best practices [11]. Quality maintenance of an HSCT center warrants added personnel, IT support, strategic, and risk communication. Quality management in HSCT can optimize survival outcomes by improving transplant practices.

#### **Conclusion**

HSCT has emerged as a defnitive treatment for a myriad of inherited and acquired hematological malignancies and solid tumors. Data management is a core competency and one of the crucial components of the HSCT program that encompasses initiating and maintaining an institutional transplant database to augment data collection, analysis, and spearheading the research. There is a growing need to adopt the best data management practices for high-quality transplant data infrastructure to determine trends for QI and the most advanced therapeutic option to optimize health outcomes (engrafting, toxicity, and survival outcome) and benchmarking. Accredited and standardized databases can provide highly valuable information and research data that cannot be obtained by other research methodologies. Existing international models are an excellent resource for adopting best practices in maintaining data management with advanced standards and capabilities. The standardization of data quality is critical to ascertain the scientifc credibility and function of outcome registries. The World Health Organization (WHO) recommendation to mandate data collection on guiding principles on cell, tissue, and organ transplantation has been a signifcant new development. The data collection and analysis would be an integral part of therapy and an obligation rather than a choice for transplant centers and will be a requirement for HSCT program accreditation. The program data standardization is vital to ascertain the scientifc credibility and reliability of a transplant program.

#### **References**


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# **Chapter 16 Maintaining the Quality Management Program**

**Nick van Sinderen**

## **General**

In this chapter, we will take a closer look with a global view on the design of a quality management system. Many standards originated a long time ago, including the FACT-JACIE standards. The FACT-JACIE standards were created to satisfy an unmet need, viz., to standardize the quality of care for patients and donors in a feld of medical intervention that had high mortality and morbidity rates and operated across international boundaries. We have now arrived in a time when quality management has become commonplace and many things have become much more regular. We even have to watch out that the various quality management systems not to overlap leading to unnecessary duplication. But do we? If you compare three wellknown standards such as

JCI, ISO15189, and JACIE, you already see in the general topics that there is overlap. Every single QM system has requirements on documents, education, adverse events, changes. And of course the new CAR-T treatments where JACIE is already very advanced but has to deal with regulations coming from pharmaceutical companies that are GxP based (Good Scientifc Practices, where "x" stands for any of the following: M, manufacturing; L, laboratory; T, tissue; D, distribution; C, clinical; PV, pharmacovigilance). Altogether, this puts considerable pressure on hospitals and their staff. So we are no longer setting up a QM system from scratch but trying to fnd a way in existing QM systems where we need to combine all of them in order to protect our departments from duplication of the same rules and regulations from different standards that are often mandatory by law. Maintaining a QMS is about to become an art. It would be good that the organizations would come

N. van Sinderen (\*)

Cellular Therapy, Antoni van Leeuwenhoek, National Cancer Institute, Amsterdam, The Netherlands e-mail: n.v.sinderen@nki.nl

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together to discuss the topics and make sure they are complementary so that valuable time can be saved which in the end is benefcial for the patient.

Establishing and maintaining a quality management system is easier said than done. It requires a lot of time, energy, and full commitment of everyone involved, starting with the (top) management. The time involved may be several years, depending on the scope (part B, C, D of the FACT-JACIE standards; see Fig. 16.1) and the clinical activity (autologous and/or allogeneic transplantation in adults and/ or pediatric, cellular therapy) of your system and the starting point. The most important pool of knowledge, however, is the education, training, and experience within the team(s). All standards are initially created by colleagues in the feld and, at least for FACT-JACIE, also further developed in the 3-year review cycle.

It all starts with the organization wanting to implement a QMS. Firstly, this ambition cannot have any result without the full support of the top management and the (medical) staff and all supporting staff including all other operational managers. Secondly, it sounds obvious, but your starting point is the knowledge and experience of your employees. A quality management system is there to help you organize it. Compare your own point of view with the standards and you will see that mostly you think the same. That shouldn't be that much of a surprise because the standards have been set up and developed by colleagues in the feld. Starting from your own professional point of view keeps you alert and will eventually increase the level of the standard. Blindly following the standards will not.

When team members are assigned tasks in the maintenance of the system, it always goes alongside their primary work. One of the statements a department can make in the policy is that everyone is responsible for the QMS and gets smaller or bigger tasks assigned alongside of the quality manager, next to their primary tasks. This could be a responsibility for a specifc document, participating in audits or maybe implementing an improvement if it is the feld of expertise. There are so

**Fig. 16.1** FACT-JACIE standards, their parts, and QMS. (With permission from EBMT)

many examples in organizations, which you will recognize, where there is no time for these extra tasks. One of the reasons for that is that the number of colleagues involved are too limited and QM tasks are many times last on the list. You can prevent this by making the number of colleagues involved bigger so that they only have one internal audit per year or have to update just a few documents instead of 20 per year. A secretary can be involved in checking transplant data because he or she provides a lot of the input during their daily work, for example by creating and maintaining fles. The advantage of this approach is that you reduce the pressure on your department, the medical team, and, therefore, also the patient. If you go one step further, you can use your QMS for education. Team up experienced with lessexperienced colleagues in every topic and you will see in the long term that many can perform the same tasks. You will create continuity and less dependence on just a few key staff.

#### **The Setup of the Quality Manual**

Here you describe your organization, policy, scope, communication, collaborations, the treatments you offer, education, and so on. Furthermore, you address the topics in a general way linked to documents that go further into detail. Fortunately, the times when the quality manual was hefty tome, that included many or sometimes even all SOPs, are almost gone. The organizational chart (both of the department and the HSCT), shows you how the communication is setup between the facilities. Also, the position of the quality manager relative to the program can be identifed here. You see everywhere in the standards that the clinical program director (CPD) is ultimately responsible for everything and must have oversight at all times. But how can this be done in practical terms? By making sure the CPD gets this information in the monthly, quarterly, and annual reports, by discussing with them regularly, including minutes of meeting, and by generating an end-of-year report that is approved by the CPD, you can cover this. It is impossible to have the CPD view every single item but it is possible to give a general overview with the ability to dig deeper when necessary. Make this visible in general in your quality manual and refer to the underlying SOP.

#### **Work Area**

The locations of parts of your scope defne a large part of your logistics. This has an infuence regarding your equipment, transport of cells, communication, and so on. It is not uncommon that parts of the HSCT chain are also a part of another department (for example, oncology or the HSCT lab is part of a bigger lab). Experience also tells us that in a small site, communication is likely to be good because the colleagues are used to really short lines and usually know each other very well. However, you may see this closeness and familiarity refected in an out-of-date documentation, and in external audits, it may appear that your document management is poor, even though everyone knows exactly what to do. What is missing is the engrained habit of documenting what you do.

#### **Material and Supplies**

It is good to see more and more that hospitals have a general way of buying goods and equipment that are validated by the manufacturer and/or during a frst (test) use. Does the equipment perform like we want to? Reports and contracts are kept in a general system. Maintenance is often done internally but sometimes also by specialized companies. For these critical items, it is important to clearly describe how you deal with urgent situations regarding backup and response time agreements with the supplier.

#### **Hygiene**

In an environment where HSCT is performed, normal cleaning is not enough. Extra hygienic measures require specialized cleaning methods. This can vary between hospitals and includes the patient rooms with air and water fltering. Analyze what information your hospital already has on cleaning methodologies and routines and add what you as a department fnd necessary with the help of the JACIE standards. By involving the hospital-wide responsible person, you will achieve a good and natural fow in the way you work and learn from each other. The result will be an extra paragraph in the hospital-wide protocol or an additional hematology protocol with a reference. It can be expected that collaboration will build up shared knowledge. Make sure to train your staff on how it is arranged.

#### **Education**

You need the right people to do the work. Their education and experience are the basics. Educational sessions (meetings, on the job training, courses, reeducation after longer leave, congresses, participation in the development of documentation) ensure that continuous education is secured. Describe what is addressed in the initial training program, also termed "introduction," for new employees. A good educational policy where colleagues see that their annual improvement is facilitated is very motivating. Encourage them also to write down and implement their plans and maybe even send it as an abstract to congresses such as EBMT. It is a great way to recognize their work.

#### **Documentation**

All the information mentioned is kept in the famous standard operating procedures (SOP). We have lots of them. The key trick is to make sure that SOPs are relevant and don't overlap with other internal SOPs or maybe general ones that are used in other departments or even across the hospital. Another challenge is also who to assign to be an author, reviewer, or authorizer. More on that topic is discussed in Chap. 3 on documentation.

#### **Changes**

Changes are a consequence of the analysis of outcome, adverse events, audits, trends, and daily experience. How to implement changes can differ per case. A standard analysis of infuence and impact – even a small one – is recommended. A process that records and documents any changes using a *change control approach* is strongly recommended, incorporating where necessary a risk assessment of the proposed change (see Chap. 18 on risk management).

#### **Validation**

The FACT-JACIE standards defne validation as, "Confrmation by examination and provision of objective evidence that particular requirements can consistently be fulflled. A process is validated by establishing, by objective evidence, that the process consistently produces a cellular therapy product meeting its predetermined specifcations." In order to achieve the aims of validation, you need to know how your processes and methods perform in order to improve and be specifc in what to improve. Validation is a tool that helps. You can divide this for example in validation of your equipment. For instance, does the apheresis machine perform within the operational parameters provided by the manufacturer? What objective measures can be used to confrm conformation to the anticipated operational parameters? For example, for an apheresis device, the harvested cell dose based on pre-harvest predictors could be a target. This is comparing expectations against real performance. How do you validate your process? That is more diffcult because you need to trace the patient from the frst visit until discharged from hospital. Nevertheless, if you combine your documents (electronic), patient fle, and all related topics, it is possible to achieve the aim. This is teamwork! By tracing the completed patient pathway, every aspect of your process should be covered. As a suggestion, take fve differently diagnosed patients per year and trace their routes and you will uncover any gaps that might be there. You could call this a process audit or a prospective risk inventory ("what if?"). The validation of your methods would be, for example, how you handle your protocols or audit cycle.

#### **Information and Communications Technology (ICT)**

The ICT process is usually covered by the hospital systems in general, and therefore it is always a challenge to get a good grip on this area. It is not uncommon that more systems are in use even sometimes in the same department. And because the HSCT chain can cover more departments, you can run into this problem. Together with the other departments and the ICT department, you need to fnd a way for good communication and fne-tuning. For instance, there may be more than one document management system, different processes in adverse events, different colleagues responsible, and so on. Solutions for defciencies on this topic mostly start with the upper management in deciding how the process is changed. Due to the many responsibilities and complicated multiple systems managed by the ICT department, you really need to make a solid case on why implementing changes are necessary. Finally, a contingency plan in case of a general ICT system shutdown is an absolute must-have.

#### **Meetings**

Meetings and evaluations shows your daily, weekly, monthly, and annual lines of communication. Make sure you describe the individual meetings well and who or per specialty, is attending. There is a never-ending discussion if you need attendance lists or not; however, a list does help a JACIE inspector quickly to determine whether important meetings such as transplant operational planning meetings, QM meetings, and morbidity and mortality meetings are attended by suffcient representation of the department. In particular, to demonstrate that the CPD has oversight, a list provides this evidence. Anything that helps during the JACIE inspection will improve the effciency of the inspection. Where electronic patient fles are in place, you can also be able to see when a treatment/patient was discussed and by whom [not a good way to have oversight]. The best thing to do is describe this in your meeting overview or the protocol related. You need to fne-tune it to your own situation and improve by your experiences.

#### **Outcome**

Analysis of treatment outcomes are done on different levels – on a daily basis and over the long term. It varies from discussing a single patient to aggregate outcome results. Together with any benchmarking schemes in your country and or via the EBMT registry, you will get a good insight into how well the program is performing.

Outcome analysis, a summary of important outcomes and review, will teach the transplant team a great deal by spotting trends and helping to indicate where to make changes. A strong advice would be to categorize generally which sounds obvious but make sure you categorize the same as your adverse events, complaints, audit fndings, and so on. If you do this for your whole department, you will be even more capable of making global as well as detailed analysis. For further details, see the chapter on outcome in this book.

#### **Risk Assessments**

Risk assessment is a crucial tool that must be a core component of any transplant and cell therapy program. Risk assessment is essential in managing change as part of change control and when introducing a new process, procedure, or therapeutic intervention into the program. The challenge is to keep the risk assessment process simple. You easily drown in too many risk assessments. Defne what is important and how you want to do it. A risk assessment is also the result of a discussion about a change in treatment from which the why and how you will put in the (electronic) patient fle, without saying it is a risk assessment, so partly what you do on a daily basis.

#### **A Practical Example**

In JCI, you are required to use the RSVP (reason, story, vital signs, plan) method for verbal and written communication. While implementing this in a facility, the team realized that they already did this through the electronic patient fle, not realizing it was a method. The facility saw this as common sense to do so.

Again, it is important to restate that you always need to check what is already in place before implementing a "new" change. What the exact best way is you will learn during implementing and evaluating and can differ per facility.

#### **Audits**

There are many audits described in the JACIE standards (see Fig. 16.2) and they will need fne-tuning depending on the scope of your activities. Do not hesitate to combine audits when possible. They are a great tool for learning and should form part of the educational program for staff. One approach for well-funded departments is to set up a team of auditors with members of every discipline. Make teams with a focus to learn from each other. An alternative strategy is to have a small group of individuals with audit training who help less senior staff members such as trainee doctors and nurses who are given individual audit topics to prepare and present to the department. Audit experience is a mandatory requirement in many countries for trainee medical staff and provides good opportunities to gain experience not only in the audit cycle but also in presentation of the completed audit. Good audits can be

**Fig. 16.2** Critical processes that must be audited. (With permission from EBMT)

submitted as abstracts to meetings such as the annual EBMT meeting. The impact that this can have on awareness of processes, who is doing what and implementing changes, is underestimated. Here are some examples of audits that must be performed regularly.

Some take aways:


**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

# **Chapter 17 Training Programme**

**Ilknur Kozanoglu and Songul Tepebasi**

Cell therapy guidelines and standards, for staff training and quality control, are outlined in the European Union (EU) Directives and by other international agencies [1–5]. In addition to staff qualifcations and training, the directives also require documented evidence of the qualifcations of the trainers [4].

Educational activities aimed at developing staff knowledge and skills [6] are fundamental for safe and effective cell therapy. Such educational activities can facilitate the manufacturing of a cost-effective product while improving overall process and improve management. Appropriately trained staff have more self-confdence, a greater sense of accomplishment and ability to fulfl personal goals, and better communication and leadership skills [7]. High-quality and motivated cell therapy staff are indispensable regarding developing and maintaining an effective QM system. Therefore, it is advantageous for cell therapy staff to have continuous training and receive competency evaluations at regular intervals.

## **Types of Education**

FACT-JACIE has established international standards for cell therapy, including the following training and education requirements for personnel.

S. Tepebasi

I. Kozanoglu (\*)

Department of Physiology, Baskent University Medical Faculty, Ankara, Turkey

Adana Adult Bone Marrow Transplantation Centre, University of Baskent, Adana, Turkey

Department of Quality Management, Adana Adult Bone Marrow Transplantation Centre, Adana, Turkey

M. Aljurf et al. (eds.), *Quality Management and Accreditation in Hematopoietic Stem Cell Transplantation and Cellular Therapy*, https://doi.org/10.1007/978-3-030-64492-5\_17

#### *Orientation Training*

This includes activities to introduce new employees to their colleagues and the treatment centre. The aim, history, philosophy, rules and procedures of the centre should be reviewed with all new staff. Information about human resources policies to include business hours, staff support services, payroll procedures, overtime requirements and benefts are provided, together with information on the physical capacity of the organisation. Specifc orientation training for staff working in cell therapy should cover general therapeutic principles for each area involved in cellular therapy as well as the functionality of the cellular therapy clinical units within the centre. All training should be clearly defned in the standard operating procedures. To facilitate orientation, a handbook could be provided to all personnel to ensure compliance (Table 17.1).

#### *Initial Training*

After attending a general facility orientation, initial hands-on training of new personnel should begin. It is especially important that personnel, who will be performing critical procedures, clearly understand the work that they will be undertaking.


**Table 17.1** Example orientation training programme for new personnel in a cell therapy unit

Initial training should focus on relevant scientifc and technical material, organisational structure, the QM system, health, and safety rules, and ethical, legal, and regulatory policies [4].

Moreover, the initial training should allow suffcient time to grasp the concept and application of the treatment processes at various interval of patient care. For processes where minimising error is critical, training should be repeated, at specifc intervals with assigned knowledge and skills sign-offs, to ensure that personnel fully comprehend the content.

#### *Continuous Education*

Continuous staff training, both personally and professionally, is essential to ensure that both staff and the department keep abreast of the latest developments in cellular therapy [4]. Centers can develop and apply their own continuous education programs or use methods based on international standards. New developments in cell therapy occur constantly, and training will facilitate the adoption of new methods and processes by personnel. Continuous training is a dynamic process that ensures that the centre itself is committed to continuous growth and development.

According to FACT-JACIE, key personnel should participate in a minimum of 10 hours of educational activities related to cell therapy annually, and continuing education should include, but not be limited to, activities related to hematopoietic stem cell therapy. Appropriate continuing education activities [4] include the following:


#### **Training Methods**

#### *Theoretical Education*

All cell therapy centres should provide theoretical training with a predetermined purpose, method, and content (Table 17.2).


**Table 17.2**Planned training to be delivered over a 6-month period in a clinical unit

## *Practical Training*

Mistakes made during cell therapy can be fatal to patients and may also lead to product loss. Thus, practical training should be provided to personnel involved in all relevant procedures but especially those considered critical.

## *Rotation Training*

Rotation of personnel between departments and roles will enhance experience, skills, and knowledge. The aim is to familiarise employees with the functions, rules and procedures of all departments included in the rotation cycle. Rotation training constitutes a holistic approach to the training of new personnel, who will engage in activities involving a variety of disciplines.

#### *Conferences*

Given the rapid advances in cell therapy treatments and methods, information exchange at the international level is essential to remain up to date. This can be accomplished through attendance at relevant courses and conferences.

## *Case Training*

Case training requires personnel to analyse cases, identify problems and discuss possible solutions with their colleagues; this process allows personnel to readily apply their knowledge and skills.

## *Online Training*

The information and technologies available through the internet have become indispensable tools for modern education. Online training has increased dramatically due to ease of access and the possibility of training many people in a single session. In addition, participants can provide feedback and their profciency can be assessed automatically [8].

#### *Standard Operating Procedure (SOP) Training*

Cell therapy personnel should be familiar with the SOPs in a QM system. Personnel should be trained in the use of these documents so that they can be effectively applied, when needed.

#### *Unplanned Training*

Unplanned training may be required to address repeated errors, following an inspection by an auditor, or in response to events occurring on a particular day. The location and timing of unplanned training are inherently undefned but should be recorded by the QM system, as required.

#### **Trainer Qualifcations**

The most important factor in the effectiveness of training is the trainer. International standards for cell therapy do not specify the qualifcations required by a trainer. However, he or she should have suffcient skills, experience and knowledge of the topic to be taught and should be able to demonstrate specifc competencies on request by auditors. Centres should not only employ qualifed educators but also defne their own training methods according to their QM plans. The effectiveness of the trainer should be assessed using a survey of training participants.

#### **Determination of Training Needs**

The training of personnel starts by determining their needs. The required training should then be delivered in accordance with legal and institutional requirements. The training required for maintenance of unit activities (e.g. SOP training) should consider not only what is needed to perform the tasks required by that unit but also the necessity to develop new skills [1–4].

The types of training needed by employees can be assessed by means of surveys, interviews, observation and performance tests. Ideally, a training commission should be created by each centre to determine training parameters including duration, location, method and certifcation (Table 17.2).

After training needs have been determined, a training programme should be planned and discussed with trainers. Decisions should then be made regarding who should participate in the training, and its format, delivery date/time and location. Training programmes should be run once or twice a year, although this will depend on the identifed needs and capacity to deliver training. All training should be operationally and clinical focused on the cellular therapy programme.

#### **Documentation of Training**

As discussed above, training should be conducted in accordance with the training programme. If a training session does not take place in accordance with the plan, the reason for this should be documented; postponing the session until the next training period should also be considered.

All training activities should be documented in accordance with the QM system. Every stage of the training procedure should be recorded and archived, according to the regulations and standards of the individual centre.

#### **Training Evaluation**

Evaluation of the quality and outcomes of training are essential to assess how much information has been imparted to personnel. Clear and quantitative assessments facilitate determination of the effectiveness of the training.

The criteria used in training evaluations should be defned in the training plan. Signifcant work aimed at quantifying the learning that occurs during training has been carried out by Kirkpatrick, who assessed four different areas: (i) participants' responses to education, (ii) learning effcacy, (iii) participants' behaviour after training and (iv) training outcomes [9].

The optimal methods for evaluating training outcomes for key therapy personnel should be determined to ensure patient/donor/product safety. Indirect evaluation methods, including product effectiveness and patient outcomes, can also be used.

In addition, training sessions should be recorded to allow subsequent evaluations thereof, whether by testing or observing the participants.

#### **Conclusion**

Training is a critical part of any QM system and can contribute to continued progress in the feld of cell therapy. International standards have defned the training required for key cell therapy personnel. Within this framework, all centres should establish their own procedures for conducting and evaluating training. The procedures should be dynamic and meet the needs of the individual unit.

#### **References**


**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

# **Chapter 18 Risk Management**

**Joaquim Vives and Judit Amposta**

# **Abbreviations**


J. Vives (\*)

J. Amposta Freelance Quality Consultant, Mataró, Barcelona, Spain e-mail: jamposta@bioqualy.cat

Servei de Teràpia Cel·lular, Banc de Sang i Teixits, Edifci Dr. Frederic Duran i Jordà, Barcelona, Spain

Musculoskeletal Tissue Engineering Group, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain

Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain e-mail: jvives@bst.cat


#### **Defning Risk in Cell Therapy**

A risk is defned as a combination of the probability of occurrence of harm and the severity of that harm [1]. It is recognised that complex processes are involved in cell therapy embracing a life cycle that encompasses people, facilities and equipment, reagents and materials, documents, and procedures. The risk of altering any critical quality factors related to safety (that is, for any of the stakeholders involved) and effcacy of the cell-based product administered to patients need to be taken into consideration in order to improve established workfows and pursue better therapies. In our context, major risks to be considered are those affecting the health of donors and patients, so all efforts should focus on the identifcation of risks that may critically impact on their health and the cost of cell processing to make improved therapies affordable. Fortunately, existing pharmaceutical standards, such as GxP (Good Scientifc Practices, where "x" stands for the following: M, manufacturing; L, laboratory; T, tissue; D, distribution; C, clinical; PV, pharmacovigilance), already developed tools for risk management that can cover not only the critical quality attributes (CQA) of the cellular products but all the activities involved in the entire process, from the procurement of starting material from donors to the administration in patients and their follow-up, that is "from vein (of donor) to vein (of patient)" [2–4].

The advent of a new generation of cell-based medicines, in which cells are substantially manipulated, even genetically (e.g. MSC, CAR-T cells, iPSC), poses major risks and therefore robust methods need to be established and validated to ensure safety consistently [2, 5–7].

The Foundation for the Accreditation of Cellular Therapy (FACT) and Joint Accreditation Committee of the International Society for Cell and Gene Therapy (ISCT)-Europe & European Society for Blood and Marrow transplantation (EBMT) (JACIE) have published guidelines that incorporate risk-based assessment as a key element to consider in every critical decision [8]. However, it is important to note that the acknowledgement of risks does not make an unsafe or a low-quality product into a safer one. In other words, risk assessment is useless unless a proactive attitude and willingness to make a (positive) difference exist. This means that risk management is not adding an additional documentation burden but a critical quality tool that holds the potential to assist us to better understand the weakest points of processes involved in the life cycle of cell therapy treatments. Then, improvements can be implemented upon accurate documentation of processes, analysis of risks, and defnition of suitable actions for mitigation. Several other factors must be taken into consideration, ranging from the design of facilities and the manufacturing process to adequate personnel training and effcient documentation system, to name a few [3]. The main goal of following a risk-based approach is to improve decisionmaking and lead to a more effective and effcient management and oversight framework, as well as optimal use of institutional resources.

Quality risk management (QRM) is a tool recognised and incorporated in mandatory and voluntary accreditation schemes, GMP being the strictest standard in this regard [8]. GMP is of mandatory application in drug manufacturing and, therefore, they are also applied to substantially manipulated cell-based products, which are considered medicines by most regulatory authorities [6, 9]. QRM is in fact the adaptation of the topic Q9 from the guidelines issued by the International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use. This is the major guideline providing principles and examples of tools for QRM that can be applied to different aspects of pharmaceutical quality. Importantly, ICH Q9 provides advice on the use of QRM considering that the level of effort and formality must be in accordance with the level of risk [1].

Guideline ICH Q10 (on the pharmaceutical quality system) establishes the structure to build an effective pharmaceutical quality system to support pharmaceutical development and manufacturing across the product life cycle incorporating QRM as a facilitator agent. Here it is important to note that the earlier we start considering risks, the better the management of processes could be expected in the future and, subsequently, this would lead to safer treatments. Likewise, voluntary accreditation schemes (e.g. FACT-JACIE, ISO9001) incorporate QRM, thereby showing some similarities and/or equivalences between standards [8].

#### **The Quality Risk Management Process**

In cell therapy, QRM can be defned as the systematic process for risk assessment, risk control, risk review, and communication of the quality risks in the processes involved during the entire life cycle of the treatment. A standardised and robust system is needed to identify risks, determine their potential hazards, and reduce or eliminate those that are unacceptable.

According to current FACT-JACIE guidelines, the identifcation of a risk can be made by providing a description and establishing the context or scope, so all the possible risks are identifed and the possible ramifcations or impact in all areas are analysed thoroughly [10]. Once the context or scope has been established successfully, the next step is identifcation and evaluation of potential risks by either source or effect. During source analysis, the source of risks is analysed and appropriate mitigation measures are put in place. This risk source could be either internal or external to the system. During problem analysis, the effect rather than the cause of the risk is analysed. Once the risk has been identifed, it must be assessed on its potential criticality or on their likelihood of occurrence and the potential impact by either quantitative or qualitative evaluation, as shown in Table 18.1 and further described in this section.

There are many different approaches to calculating risk, and there are tools that can help assist in defning the probability of the effect occurring, the root cause, effects, and magnitude of risk under different scenarios. Risk Evaluation and Mitigation Strategies (REMS, in the USA) or Risk Management Plan (RMP, in the EU) may include (but are not limited to) detailed procedures for providing education and instructions to personnel involved (including donor and patients), monitoring patients, managing adverse events, and reporting outcomes to manufacturers. Once the risk assessment is established, an RMP can be developed and implemented. It comprises the effective controls for mitigation of risk. Risk management involves the justifcation and rationale for accepting risks and how to manage their impact if applicable. This can often be established in a simple one-page document for change with low impact and risk.

The QRM must be integrated into the pharmaceutical quality system to be properly documented and become a consistent tool for improvement. Risk management must be proactive rather than reactive, and it must be incorporated into the culture of prevention of the organisation. One could say that the process of QRM takes the steps depicted in Fig. 18.1, which are taken from current GMP [11] and further discussed next.

#### *Risk Assessment*

Risk assessment consists of the identifcation of hazards and the analysis and evaluation of risks associated with exposure to those hazards. Quality risk assessment begins with a well-defned problem description or risk question. In doing an effective risk assessment, the robustness of the data set is important because it determines the quality of the output. The document refecting the risk assessment can be completed by following three successive steps, as described next.

*Step 1: Risk identifcation* The purpose of this phase is to recognize and record the risks of the situation being evaluated, identifying the origin of the risks and their causes. It aims to answer the question: What could go wrong? Risk identifcation


**Table 18.1** Methods commonly used for identifcation of risks

*FMEA* failure mode effects analysis, *FMECA* failure mode, effects and criticality analysis, *FTA* fault tree analysis, *HACCP* hazard analysis and critical control points, *HAZOP* hazard operability analysis, *PHA* preliminary hazard analysis, *RRF* risk ranking and fltering

methods that may be used include reviewing of historical data, brainstorming, elementary cause, and assign consequences (e.g. fshbone Ishikawa, diagram, failure mode/effect table), fault tree analysis, process map, fow charts, just to name a few.

*Step 2: Risk analysis* Estimation of the risk associated with the identifed hazards can be either a qualitative or quantitative process of linking the likelihood of occurrence and severity of harms. In some risk management tools, the ability to detect the harm (aka. detectability) also contributes to the ability to estimate risk. Risk analysis aims to answer the following questions: What are the chances (probability) of happening? What would be the consequences?

There are several methods suitable for the management of risks. From these, the next seven recognised tools are considered relevant in the cell therapy feld (further described in Table 18.1).


Depending on the particular situation to be evaluated, one method or the other will be chosen. When the risk is expressed quantitatively, a numerical probability is used. Alternatively, risk can be expressed using qualitative descriptors, such as "high", "medium", or "low", which should be defned in as much detail as possible. The application of statistical tools (e.g. Pareto charts, histograms, Process Capability Index – CpK, dispersion graphs) together with these risk management tools helps to obtain additional information.

*Step 3: Risk evaluation* The purpose of this fnal step is to compare the identifed and analysed risk(s) against given risk criteria.

#### *Risk Control*

Risk control involves the decision-making of either (A) reducing the risk or (B) accepting and managing the residual risk. Ideally, identifed risks will be reduced to acceptable levels, always remembering the premise that the effort and resources applied must be proportional to the risk. It aims to answer the following questions: Is the risk beyond the acceptance level? What can I do to eliminate or reduce the risk? What is the appropriate balance among benefts, risks, and resources? Are there any new risks introduced because of the actions taken to control a risk?

**Fig. 18.1** Overview of quality risk management along the life cycle of cell therapies

*Step 1: Risk reduction* Here we must focus on actions to decrease severity and the likelihood of any harm occurring when it exceeds a specifed (acceptable) level (Fig. 18.1). This step may imply a redesignation of the process (e.g. inadequate controls, lack of robustness of the process).

*Step 2: Risk acceptance* Risk acceptance is a decision to accept risk after the evaluation of severity, likelihood, and the detectability of hazards. Risk acceptance can be a formal decision to accept the residual risk (risks well specifed) or it can be a passive decision in which residual risks are not specifed (risks are part of the natural variability of the process). For some types of harms, even the best-quality risk management practices may not help to eliminate the risk completely, but only reduce it partially. This (specifed) acceptable level may depend on many parameters and should be decided on a case-by-case basis. The rationale behind such a strategy should be documented, residual risk described, and appropriate management strategies put in place.

#### *Risk Review*

It is very important to carry out continuous monitoring and verifcation of risk management to identify changes in the assessed situation. This could generate new risks or affect the effectiveness of the initial risk management plan. We must be aware that the probability of risk and the risks themselves will change when the conditions change. Risk review serves as a verifcation and is key to promote the concept of continuous improvement. Risk review is easier to perform if there is someone in charge of monitoring the progress of the implementation of the action plan . Importantly, this step adds value to the risk analysis management.

#### *Risk Communication*

Risk communication is the act of sharing information on risk and risk management between the decision makers and stakeholders involved in critical steps of the cell therapy process (as discussed in section "Stakeholders Involved in Risk Management"), thus ensuring an effective information fow. Parties can communicate at any stage of the risk management process (dashed arrows in Fig. 18.1). The output of the quality risk management process should be appropriately communicated and documented (solid arrows in Fig. 18.1). The included information might relate to the existence, nature, form, probability, severity, acceptability, control, treatment, detectability, or other aspects of risks to quality. Communication need not be carried out for every risk acceptance. Risks which are subject to frequent changes by trend need to be reported more frequently than constant risks.

#### **Stakeholders Involved in Risk Management**

Activities involved in risk management of cell therapy processes should be carried out by multidisciplinary teams, including experts in the different areas (e.g. quality assurance, process and quality control, medical management, pharmacy) and a risk management coordinator. It is very important to establish well-defned, up-to-date standard operating procedures (SOP) and having the necessary resources. This team should meet on a regular basis to keep the risk analysis in a living state, which is updated with the latest data available (e.g. incidences, non-conformities, bio-vigilance).

#### **Illustrative Examples of Specifc Applications**

Risks in cell therapy are diverse due to the complexity of the whole process and may impact on any critical step along the life cycle. A good understanding of the six Ws (summarised in Box 18.1) is key to realise the potential of risk management. Some explanatory examples are described next to illustrate the applicability of QRM and its potential to support continual improvement.

#### **Box 18.1 The Six W of Risk Management in Cell Therapy**


#### *Related vs. Unrelated Donors*

Donation of HSC from related donors (RD) is associated with higher occurrence of adverse events (including death) than in unrelated donors (UD) [12]. Circumstances particularly applicable to RD are complex and contribute to increased risk. Risks include the lack of regulatory guidance, logistical and fnancial barriers, lack of the beneft of anonymity, close relationship with the transplant recipient, and the consequent pressure to donate. RD tend to be older than UD and therefore more likely to have morbidities. The impact of quality management in driving change was confrmed by Anthias and collaborators, who reported that improvements observed in donor care were successfully achieved in areas where recent FACT-JACIE standards were introduced [12]. Continual improvement can be further achieved by gradual understanding of risks, particularly present in each individual institution.

#### *Processing of Cell Therapy Products*

Cell-based therapies are rapidly evolving from traditional HSCT to current genetically engineered immune cells and mesenchymal stem cells [13, 14]. Therapeutic activity of cell-based products is susceptible to intrinsic biological variability, as opposed to traditional pharmaceutical drugs, such as small molecules or biologicals. In this context, it is crucial to deeply understand the cell's critical quality attributes (CQA) (directly impacting on the product's safety profle and clinical effcacy) and how these are affected by any disturbance in the process [15]. Moreover, cell manufacturing is a poorly automated process, prone to operatorintroduced variations, and affected by heterogeneity of the processed organs and tissues and batch-dependent variability of reagent effciency [16]. In a recent study, we reported the impact of risks associated with main failure groups (that is process, equipment, personnel, documentation, environment, reagents, and materials) on the specifcations of a mesenchymal cell-based product with multiple applications including the management of acute graft-versus-host disease (GvHD) [17]. From all risks that were identifed, those associated to cell processing and apparatus were high in the initial steps of product manufacturing but replaced by risks associated to operator errors at later stages of production. In this study, the risk analysis was performed following FMEA/FMECA and actions were prioritised using a simple Pareto chart, proving to be a powerful method within a clinical cell therapy manufacturing context, as well as an ideal vector for prompting alternative and proactive improvement processes [18, 19]. Moreover, the intrinsic fexibility of the method makes it ideal for critical risk assessment in all processes related to the entire life cycle of the cell-based product, thus allowing to properly identify risk priorities and corresponding control activities, supports the identifcation of necessary actions for quality improvement, and provides a specifc model for guidance of cell transplantation centres and cell processing facilities approaching risk management for the frst time, especially if lacking personnel with specifc risk analysis expertise [16, 18, 19].

#### *Patients*

From EBMT registry data, Snowden and collaborators confrmed the correlation of occurrence of new centre accreditation with improvements in patient survival and reduction of procedural mortality, demonstrating the clinical benefts of adoption of quality standards [20]. Consistently, transplant centres in advanced phases of FACT-JACIE accreditation are linked to signifcantly higher survival rates, independent of year of transplantation or other risk factors [21]. Therefore, the implementation of FACT-JACIE standards contribute to improved processes and mitigate existing (maybe hidden) risks. In addition to general QRM, specifc tools have been created as is the case of the EBMT risk score, providing a simple way to assess benefts and risks of HSCT for an individual patient pre-transplant, by assessing only fve factors (namely, age of the patient, stage of the disease, time interval from diagnosis to transplant, HLA matching, and gender of donor and recipient). Higher risks are observed for an individual patient with increasing score from 0 (best) to 7 (worst) in an additive way [22]. Integration of the EBMT risk profle into the risk assessment should guide in the decision process, ultimately leading to a better decision in the selection of transplant patients.

#### **Final Remarks**

Remarkable improvements can be achieved by following simple risk assessment tools. Growing evidence shows that the systematic and comprehensive evaluation of risks impacting on safety and effcacy of cell therapy contributes to proper management of risk affecting donors and patients. Institutions already accredited for standards incorporating QRM are best positioned to drive change in cell therapy by a systematic risk-based approach. Rather than following each of the different quality guidelines and standards separately, we encourage institutions to customise their own methodology of QRM to ft them into the unique characteristics and needs of their institutions. Importantly, quality management systems need to be fexible enough for continuous evolution from traditional HSCT and stay open to the future trends in cell and gene therapy.

It should be noted that Lean Six Sigma strategies are fully compatible with QRM. In fact, some hospitals and blood and tissue banks are already using these tools and we expect this to become the trend if they both are dynamic and facilitate continual improvement in the life cycle of the treatment.

#### **References**


**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

# **Index**

#### **A**

Accreditation process committee members, 134 action plan, 127 cellular therapy standards committee, 134 competent authorities, 125 documentation and key agents, 133 EBMT database, 124 inspectors, 133 monitoring, 125, 127 phases of inspection phase, 130, 131 post-inspection phase, 132 pre-inspection phase, 127–130 planning, 125 post-accreditation period, 132–133 pre-inspection phase, 123 process fow, 133 quality management system, 124 timetable, 126 Adverse events (AE), 89, 94 Adverse reaction, 90 American Society of Transplantation and Cellular Therapy (ASTCT), 2–3 Application form, 128 Asian Pacifc Blood and Marrow Transplantation Group (APBMT), 3 Audit calendar, 27–28 Audit plan, 28 Audit report, 30, 32 Auditing actions, 32 audit calendar, 27–28

audit plan, 28 audit report, 30, 32 communication of result, 32 conducting audit, 28 corrective action plan, 33 defnition, 25 formal closing meeting, 28 on-site vs. document, 26, 27 purpose, 25 scope of, 25 Auditor requirements, 27

#### **B**

Biological product deviations (BPD), 90, 93–96

#### **C**

C8 Apheresis collection process controls include, 102 Cell reinfusion, 91 Cell therapy, 157, 166 Cellular therapies, 137 Cellular therapy standards committee, 134 Center for International Blood & Marrow Transplant Research (CIBMTR), 3 Change control, 41 Clinical policy group, 15 Clinical program controls, 102 Clinical program director (CPD), 20 Colours HCT programme, 111 Contract/commercial agreement, 63, 64

© The Author(s) 2021 177 M. Aljurf et al. (eds.), *Quality Management and Accreditation in Hematopoietic Stem Cell Transplantation and Cellular Therapy*, https://doi.org/10.1007/978-3-030-64492-5

Corrective and preventive actions (CAPAs) BPD, 90, 93–96 complaints, 90 corrective, preventive action, 91–93 investigation and analysis, 90 prevention of errors, 89 report deviations, 92 reporting complaints errors, 94 SAE, 90 types of incidents, 91

#### **D**

Data management cultural sensitivities/communication, 143 data processing, 142, 143 data utilization, 144 dynamics of, 140 fundamentals of, 139–140 funding and sustainability, 144 high-quality HSCT program, 138, 142 HSCT, 137, 138, 141 intellectual property rights, 144 pharmacovigilance, 144 publications, 144 quality assurance and CQI, 145 regulatory compliance, 143, 144 SOPs/IPPS/playbook, 142 strengths of, 141 trained/qualifed personnel, 142 Document control, 111, 112 Document management system (DMS) create and review documents, 20 document structure, 19 duplication of requirements, 21 education and, 22–23 hygiene and safety policies, 18 ICT systems, 22 in-document URL hypertext links, 18 in-house expertise, 18 JACIE, 23–24 paper documents, 22 pre-printed orders and worksheets, 17 setup of quality manual, 18 transplant program, 17 workfow, 19–20 Donor lymphocyte infusion (DLI), 4

#### **E**

Effective communication, 55–56 European HSCT, 5 European Society for Blood and Marrow transplantation (EBMT), 2, 166

#### **F**

FACT accreditation systems, 4 FACT-JACIE international standards, 3 FACT-JACIE standards, 9, 101, 111, 114, 120, 126, 147, 148, 151

#### **G**

Gentleman's agreement, 62 Global donor identifer (GRID), 87

#### **H**

Haematopoietic cell transplantation (HCT), 123 programs, 78, 113 Haematopoietic cellular therapies, 55 Haematopoietic stem cells transplantation (HSCT) impact, 5 program, 89 quality, 1, 2 standards, 2–4 Healthcare performance measurement, 70–71 Holistic outcome analysis, 48 Hospital-wide electronic patient records (EHRs), 22

#### **I**

Immune effector cells (IEC), 4 Information and communications technology (ICT), 152 Interim audit, 27 International Society for Cell and Gene Therapy (ISCT), 166 International Society for Cellular Therapy (ISCT), 2

#### **J**

JACIE document management, 23 JACIE standards, 38, 153 Job descriptions, 56–58 Joint Accreditation Committee – ISCT & EBMT (JACIE), 2

#### **K**

Key performance indicator (KPI), 43, 71, 78 Key personnel, 54–55

#### **M**

CM8 Marrow collection process controls, 102

Index

Memoranda of Understanding (MoU), 61, 62 Multidisciplinary group, 15

#### **N**

Near-miss reporting system, 90

#### **O**

Occurrences, 115 Organisation(al) chart, 12, 13, 54 Organisational structure, 54 Outcome analysis, 113 collecting data, 44, 46 comprehensive tracking system, 47 holistic outcome analysis, 48 intended outcome measure, 43 long-term review mortality, 50 long-term trending review engraftment, 48 quality summary report, 50 reviewing data, 49–51 sample of data presentation, 45, 46 staff-based outcome analysis, 49 standards, 44

#### **P**

Paper-based DMS, 22 Performance measurement (PM) accountability and performance, 69 administrative focus areas, 81 annual operational dashboard, 78 challenges HCT programs, 80 clinical SCT program, 80–81 criteria for selection, 75, 76 dashboard basics for quality, 79–80 healthcare performance measurement, 70–71 indicators, 77 KPI, 78, 79 life cycle, 71, 72 outcome measure, 77 performance score, 74–75 process, 73–74 process measure, 76 scorecard metrics, 79 SCT program, 70, 75–78 SCT quality KPI, 80 structural measure, 76 Performance score, 74–75 Personnel fles, 58

Personnel requirements centralised and active communication network, 53 effective communication, 55–56 job descriptions, 56–58 key personnel, 54–55 organisational chart, 54 organisational structure, 54 personnel competency, 55, 56 personnel fles, 58 responsibility and task awareness, 55 signature lines, 58 Plan-Do-Check-Act (PDCA), 19 Process indicators actions, 104 communication, 105 defnition, 99, 102 indicator's table, 103–104 measure and timing, 103 outcome analysis, 103 policy, 99 process controls, 101, 102 product, 99 quality control, 100 transplant process, 100 transplant program, 101, 102 within time, 105 Process validation, 41 D8 Processing process controls, 102

#### **Q**

Qualifcation, 42 Qualifcation and validation change control analysis, 40 competency of personnel, 39 facilities, material, equipment, personnel, 38, 39 JACIE Standards, 38 periodic validation, 40 qualifed equipment, 35 and responsibilities, 37 review and approval, 40 risk assessment, 36, 38 SOP/VMP, 35, 36 test, 40 transplant program personnel, 36 validated process, 35 validation plan, 38 Quality, 42 Quality assessment, 42

Quality assurance, 42 Quality management program (QMP) audits, 153 changes, 151 critical processes, 154 documentation, 151 education, 150 establishing and maintaining, 148 hygiene, 150 ICT, 152 material and supplies, 150 meetings, 152 outcomes, 152 permission of EBMT, 154 risk assessment, 153 setup of quality manual, 149 validation, 151 work area, 149–150 Quality management system (QMS) audits, 114 business continuity policy, 116–117 clinical, collection and processing, 10 communication, 15 communication and responsibility, 11 contingency plans, 112 continuous quality improvement, 119–120 defnition, 9 document control, 111, 112 FACT-JACIE accreditation standards, 107 FACT-JACIE standards, 10 HCT programme, 109 key performance data, 113 management of occurrences, 115 management of products, 114–115 obtaining feedback, 119 organisation chart, 12, 13, 109, 110 outcome analysis, 113 qualifcation, 117 quality manager role, 14 quality risk management, 118–119 structure, 108–120 third-party collection and processing services, 12 traceability, 115, 116 training & competency, 110 types of groups, 16 validation/verifcation, 117 Quality risk management (QRM), 42, 167

#### **R**

Risk communication, 172 Risk control, 170 Risk identifcation, 168 Risk management

defnition, 166 identifcation of risks, 169 lifecycle of cell therapies, 171 patients, 174 processing of cell therapy products, 173 quality risk management process, 167–172 related *vs*. unrelated donors, 173

#### **S**

Scatter gun communications, 67 Self-assessment checklist, 128 Serious adverse events (SAE), 90 Service level agreements (SLA), 63–65, 108 Signature lines, 58 Single European Code (SEC), 87 Staff based outcome analysis, 49 Standard operating procedure (SOP), 99, 162, 172 Standards-setting organization, 5 Stem cell facility user group, 15 Stem cell transplantation, 83

#### **T**

Technical agreement, 65, 66 Third-party agreements communication, 67 contract/commercial agreement, 63, 64 gentleman's agreement, 62 MoU, 61, 62 no duplication of provisions, 66 SLAs, 63 technical agreement, 65, 66 Traceability, 115, 116 Tracking and traceability allogeneic bone marrow, 85 cellular products, 87 combining donation and product information, 87–88 comparative size of information, 86 delivery mechanism, 85 identifcation of cellular products, 83 information environment, 84–87 standardized ISBT128 label format, 86 unique product description, 85 Training programme case training, 161 conferences, 161 continuous education, 159 determining needs, 162 documentation of, 163 educational activities, 157 evaluation of, 163 initial training, 158–159

Index

online training, 161 orientation training, 158 practical training, 161 rotation training, 161 SOPs training, 162 theoretical education, 159–161 trainer qualifcations, 162 unplanned training, 162 Transplant process, 100 Transplant Registry Unifed Management Program (TRUMP), 138

**V**

Validation Master Plan (VMP), 40 Verifcation, 42

#### **W**

Workforce, 53 World Marrow Donor Association (WMDA), 3, 87 Worldwide Network for Blood and Marrow Transplantation (WBMT), 3