Guide to Cell Therapy GxP: Quality Standards in the Development of Cell-Based Medicines in Non-pharmaceutical Environments

Guide to Cell Therapy GxP

Quality Standards in the Development of Cell-Based Medicines in Non-Pharmaceutical Environments

Joaquim Vives

Barcelona, Spain

Gloria Carmona

Seville, Spain

Table of Contents

Cover image

Title page

Copyright

List of Contributors

Foreword

Preface

1. Overview of the Development Program of a Cell-Based Medicine

1. Introduction

2. Key Pharmaceutical Factors to Consider in Early Development Stages

3. TPP: Beginning with the End in Mind

4. Stages of Drug Development

5. Considering Stakeholders

6. Product Lifecycle and Portfolio Management

7. Performance Management and the Check Point Value

8. Conclusions

2. European Regulatory Framework for the Development of Cell-Based Medicines

1. Introduction

2. What Cell-Based Products are Considered as Medicinal Products? The Legal Definitions and Main Regulations Applying to Cell-Based Products

3. An Introduction to Cell-Based Medicine Development: Roadmap

4. Regional and National Institutions Supporting Cell Therapy Translational Research

5. European Regulation for Advanced Therapy Medicinal Products Not Intended to be Placed on the Market: Hospital Exemption and Its National Interpretation

6. Conclusions

3. Nonclinical Studies for Cell-Based Medicines

1. Introduction

2. Types of Cell-Based Advanced Therapy Medicinal Products and their Safety Considerations

3. Regulations and Nonclinical Studies

4. Nonclinical Assessment—The Risk-Based Approach

5. The Requirement for Good Laboratory Practice

6. General Study Design Considerations

7. Specific Nonclinical Safety Considerations

8. Conclusions

4. Good Manufacturing Practice Compliance in the Manufacture of Cell-Based Medicines

1. Outline of the Chapter

2. Quality Management

3. Documentation

4. Qualification and Validation

5. Premises and Equipment

6. Personnel and Hygiene

7. Manufacturing

8. Quality Control

9. Inspections, Audits, Complaints, Recalls, and Returns

10. Conclusion

5. Good Clinical Practice in Nonprofit Institutions

1. Introduction

2. The Elements of GCP Compliance

3. The Clinical Trial Protocol

4. The Investigator’s Brochure

5. The Informed Consent

6. Essential Documents for Clinical Trial

7. Clinical Trial Files

8. Sponsor’ Study Audit and Inspections

9. Conclusion

6. Compatibility of GxP with Existing Cell Therapy Quality Standards

1. Quality Standards in Cell Therapy

2. Adaptation of Existing Standards to GxP

3. Impact of GxP Implementation

4. Quality by Design

5. Recommendations for Optimizing Integration of QA Systems

6. Conclusions

Index

Copyright

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List of Contributors

Jacqueline Barry,     Cell Therapy Catapult Ltd, Guys Hospital, London, UK

Ana Cardesa,     Andalusian Initiative for Advanced Therapies, Consejeria de Salud. Junta de Andalucia, Sevilla, Spain

Natividad Cuende,     Andalusian Initiative for Advanced Therapies. Servicio Andaluz de Salud, Consejería de Salud, Junta de Andalucía. Sevilla. Spain

Ander Izeta,     Tissue Engineering Laboratory, Bioengineering Area, Instituto Biodonostia, Hospital Universitario Donostia, San Sebastian, Spain

Giulia Leoni,     Cell Therapy Catapult Ltd, Guys Hospital, London, UK

Fabiola Lora,     Andalusian Initiative for Advanced Therapies, Consejeria de Salud. Junta de Andalucia, Sevilla, Spain

Rosario C. Mata,     Andalusian Initiative for Advanced Therapies, Consejeria de Salud. Junta de Andalucia, Sevilla, Spain

Blanca Miranda,     Biobank Andalousian Public Health Care System Granada, Spain

Natalie Mount,     Cell Therapy Catapult Ltd, Guys Hospital, London, UK

Roger Palau,     Banc de Sang i Teixits, Edifici Dr. Frederic Duran i Jordà, Passeig Taulat, Barcelona, Spain

Arnau Pla,     CELLAB, Barcelona, Spain

Andy Römhild,     Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité University Medicine Berlin, Berlin, Germany

Rindi Schutte,     Cell Therapy Catapult Ltd, Guys Hospital, London, UK

Michaela Sharpe,     Cell Therapy Catapult Ltd, Guys Hospital, London, UK

Amy Lynnette Van Deusen,     University of Virginia, Department of Pharmacology, Charlottesville, VA, USA

Foreword

This book represents an essential guide capable of presenting and dissecting the steps of a revolution that has been taking place in cell manufacturing with a specific but not exclusive focus on the so-called hospital-based facilities.

The introduction of more stringent rules in cell-based therapeutics development started just after the mid-2000 in Europe and in other regions of the globe. This mandated new operational rules and new ways of thinking. A sort of industrial revolution in cellular therapy aimed to change the manner in which a cell-based treatment had to be conceived, manufactured, and introduced into different clinical scenarios. It was a true challenge for both the producers and the regulators.

The lines in this precious text are taking advantage of almost 10  years of these complex evolutions and experience, accompanying the reader within proper product developmental strategies that consider operational contaminations between enterprises and hospital facilities as a way to generate quality assurance systems capable of facing new regulations and providing better products in early and late clinical phases.

This gmp-ification transition was relatively easily absorbed by industries, finding more resistance in less prepared hospital environments. The authors address this aspect, outlining which ways hospital-based facilities were able to face this industrial revolution in cell manufacturing. This phase also overlapped with an unprecedented crisis in world economy investing public institutions and enterprises and negatively impacting the investments for novel therapeutic approaches, cells included.

Here, the authors give evidences on how, despite the crisis, these two words were able to adapt and share their strategies to satisfy regulatory requirements, producing a quality system for GxP implementation that is now generating products with solid legs able to walk the different paths of human diseases.

The reader is lead to a road map for product development from pre-clinical evidences to clinical translations, depicting regulatory framework in Europe with clarification on definitions and regulations for the so-called Advanced Therapeutics Medicinal Product (ATMP) manufacturing. While mostly focused on the European context, the authors attempt to reflect their guidance onto other frameworks, suggesting a need for harmonization within different regulations.

The several phases of a cell-based therapy development are described with enlightening examples. Indications of the need for preclinical strategies to assess efficacy and safety are provided—outlining how all these steps should be cell specific and disease related. Instructions on how to design nonclinical programs to valorize the power of a cell-based product and to address concerns in a risk-based approach are described in a simple but not reductive manner. All these aspects will always find a partner in the International Society for Cellular Therapy (ISCT), which I am currently chairing.

The entire book is a Good X Practice analysis, where the X-factors are represented by laboratory (L), manufacturing (M), and clinical (C) steps that should take a scientifically sound concept and translate it for patient care. In particular, one can appreciate the proposal of a consistent introduction of clinical research approaches to assess the safety and the potential of a cellular product abandoning passionate expectations to look for measurable end-points within appropriate follow-up.

My feeling is that the editors and the authors of this book have truly centered on hot topics in cellular therapeutics have collected milestone contributions. I additionally have the vivid sensation that this book will play a relevant role in educating academia and industry. Many clinicians, scientists, technicians, developers, and all cellular therapists should be grateful to these authors who were here able to share their pioneering experience in the field.

Massimo Dominici, MD,     University Hospital of Modena and Reggio Emilia, Italy,     President of the International Society for Cellular Therapy 2014–2016, Modena, April, 13 2015

Preface

The possibility of treating diseases using complete organs, tissues, or isolated cells from the very same patient or a suitable donor has been, and still is, one of the challenges that has spurred biomedical research in recent decades. Availability, immunotolerance, engraftment rate and long-term full recovery of function remain active battles.

From a historical perspective, transfusion medicine has been the first known strategy that attempted to treat patients with live cells. Since the first description of blood groups until the modern manufacturing and molecular typing, transfusion has dramatically evolved at the scientific and therapeutic levels. Millions of people today owe their lives to voluntary donors and to the current sophisticated network of blood services (https://www.ibms.org/go/nm:history-blood-transfusion).

Going one step further, the understanding that cellular therapies involve activities aiming to the long-term repair or substitution of damaged cells or tissues, it can be stated without a doubt that hematopoietic transplantation is the oldest and more widespread form of cellular therapy.

Hematopoietic transplantation was born and evolved through the early experiences of George Mathé [1], followed by the recognition of histo-compatibility antigens [2], the actual key of the current transplants universe. Finally, the systematization and positive results achieved by the Seattle group that ultimately won the Nobel Prize for ED Thomas [3] were the basis for current transplant strategies, which are the only solution for a number of lympho-hemopoietic disorders. It was the first demonstration that some cells could cure or help to cure diseases. Since the 70s, more than 40  years of research and clinical investigation have confirmed the expectations of these treatments through their different evolutions. These include not only allogeneic matched and mismatched sibling transplants but also transplants using autologous bone marrow and peripheral blood stem cells, or unrelated bone marrow or cord blood, which in a number of cases are receiving ex vivo modified products.

In parallel, research in cellular, molecular, and developmental biology (especially that on stem cells of different origin and evolutionary status) has triggered the spreading of new therapeutic approaches in the form of immunotherapy [4], gene therapy, and more recently, cellular therapies aimed at regeneration of tissues [5] and perhaps organs, consolidating a new area of complex knowledge: regenerative medicine [6].

Regenerative medicine, based on the use of cells as medicines, is evolving very intensely, creating new therapeutic opportunities but also social and economic value at a rate that has not been recently observed in other areas of science. With the conviction that cellular therapies could benefit millions of citizens, the European Union and many countries are creating specific programs and structures to promote new developments and treatments. The envisaged potential huge market has stimulated private investment in hundreds of companies, mostly new, which has duplicated in the last two years, generating an overall growth of economic value of more than 25% per year [7].

Besides scientific development, new effective treatments, and value creation, regulators and scientific societies have progressively set up a frame of laws and quality assurance systems looking for something that is inalienable: the quality and safety of products and treatments.

Again, blood transfusion has pioneered the implementation of good practices standards. The American Association of Blood Banks (AABB) released its first blood bank standards in 1957 [8], which were followed in the 80′ by standards for Cellular Therapies, Perioperative Services, Relationship Testing, Immunohematology Reference Laboratories, Molecular Testing, and Patient Blood Management being added to the standards library (www.aabb.org).

In addition, specialized societies and organizations, such as the International Society for Cellular Therapy (ISCT, www.celltherapysociety.org) and Netcord (www.netcord.org) in collaboration with the Foundation for the Accreditation of Cellular Therapy (FACT, www.factwebsite.org), have developed international standards (FACT/JACIE, FACT/Netcord) and implemented accreditation procedures. In a number of countries, local standards and other authorization/certification and/or accreditation procedures are also in place with the common aim of ensuring donor and patient safety.

More recently, the definition of a new therapeutic category within the cell therapy area, for substantially manipulated cell-based medicines, has promoted a new regulatory framework that has consolidated into specific regulations adopted by the European Medicines Agency (EMA) and the American Food and Drug Administration (FDA). These regulations, known as the Good Scientific Practices (or GxP), are steeply transposed to a number of countries and their implementation is mandatory in the development of novel cell-based therapies, similar to traditional drug development in the pharmaceutical industry. However academic and not-for-profit institutions are the ones currently taking the challenge of adapting into this new scenario and opening the door to a new era in cell therapy.

Now, the increasing knowledge in the field, new technologies, the better understanding of diseases, and the possibility of personalizing cells and tissues, in a context of complex regulatory requirements, demands for professionals with specific competencies and deep understanding of this matter.

This is precisely the contribution of the present Guide to Cell Therapy GxP, addressed to any person working in the field, where the authors sew the key elements that compose the puzzle of this, I would say, revolutionary area of knowledge and patient care.

Joan Garcia,     Divisi de Terpies Avanades/XCELIA, Banc de Sang i Teixits Barcelona, Spain

Blanca Miranda,     Biobank Andalousian Public Health Care System Granada, Spain

References

[1] Mathe G, Jammet H, Pendic B, Schwarzenberg L, Duplan J.F, Maupin B, et al. Transfusions and grafts of homologous bone marrow in humans after accidental high dosage irradiation. Rev Fr Etud Clin Biol. March 1959;4(3):226–238.

[2] van Rood J.J, van Leeuwen A. Major and minor histocompatibility systems in man and their importance in bone marrow transplantation. Transpl Proc. September 1976;8(3):429–436.

[3] Thomas E.D, Buckner C.D, Rudolph R.H, Fefer A, Storb R, Neiman P.E, et al. Allogeneic marrow grafting for hematologic malignancy using HL-A matched donor-recipient sibling pairs. Blood. September 1971;38(3):267–287.

[4] Rosenberg S.A, Restifo N.P. Adoptive cell transfer as personalized immunotherapy for human cancer. Science. April 3, 2015;348(6230):62–68.

[5] Orlando G, Soker S, Stratta R.J, Atala A. Will regenerative medicine replace transplantation? Cold Spring Harb Perspect Med. August 1, 2013;3(8).

[6] Lysaght M.J, Crager J. Origins. Tissue Eng Part A. July 2009;15(7):1449–1450 27.

[7] Lanphier E. State of the advanced therapies industry remarks. Paris: Alliance for Regenerative Medicine Summit; March 2015.

[8] Sibinga C.S, Das P.C. Quality assurance in blood banking and its clinical impact. Boston: Martinus Nijhoff Publishers; 1984.

1

Overview of the Development Program of a Cell-Based Medicine

Arnau Pla     CELLAB, Barcelona, Spain

Abstract

The success in bringing to the market a new medicine in a timely and cost-effective manner relies on a proper product development strategy. Public institutions lead the development of cell-based therapeutics up to early stage clinical trials without the resources found in biotech and pharma industries. This may explain the reduced number of cell therapies approved and their disastrous financial performance in terms of revenues. Apart from understanding the whole development process, there are a couple of basic tools (such as the target product profile) and important concepts (e.g., freedom to operate) that can help to improve the early development process in a nonpharma environment and make it sound to investors for further developments up to regulatory approval for commercialization. In this chapter, we will present and discuss the series of milestones required to make an academic achievement into an approved clinical therapy.

Keywords

Advanced therapy medicinal product; Cell-based medicine; Licensing; Product development; Product lifecycle; Target product profile

Chapter Outline

1. Introduction 1

2. Key Pharmaceutical Factors to Consider in Early Development Stages 4

3. TPP: Beginning with the End in Mind 5

4. Stages of Drug Development 6

5. Considering Stakeholders 8

6. Product Lifecycle and Portfolio Management 9

7. Performance Management and the Check Point Value 10

8. Conclusions 11

References 12

Glossary 13

List of Acronyms and Abbreviations 13

1. Introduction

The goal of pharmaceutical product development is to establish the formulation composition and define its manufacturing process to consistently deliver a drug product. This drug product has to meet appropriate quality attributes required for its intended efficacy and safety profile. In addition to basic quality requirements, the commercial success of a drug product, and by extension its lifecycle, is determined by other key parameters such as patents, market, prices competence, regulatory changes, and others that must be carefully considered during early development stages. Pharmaceutical and biopharmaceutical industries have developed systematic approaches to fulfill these complex requirements. In contrast, the newborn cell therapy industry, closely linked to academia, should develop novel approaches to address this major challenge [1].

Although there are extensive resources and efforts devoted by many companies, to date, there are few cell therapy products licensed in Europe and in the United States (Table 1). This fact reflects the great complexity of developing such type of treatments. However, great hopes are invested in the emerging field of regenerative medicine and the use of cells as therapeutic agents. The term advanced therapy medicinal product (ATMP) covers the following medicinal products for human use (http://www.ema.europa.eu/ema/):

Table 1

Approved Human Cell-Based Therapeutics

With the exception of blood products, the rest include a substantial manipulation in their manufacture. Only approved human cell-based medicines were included. HPC  =  hematopoietic progenitor cells; MSC  =  mesenchymal stromal cells.

• Gene-therapy medicines: These contain genes that lead to a therapeutic effect. They work by inserting recombinant genes into cells, usually to treat a variety of diseases, including genetic disorders, cancer, or long-term diseases.

• Somatic-cell therapy medicines: These contain cells or tissues that have been manipulated to change their biological characteristics.

• Tissue-engineered medicines: These contain cells or tissues that have been modified so that they can be used to repair, regenerate, or replace tissue.

• Combined advanced therapy medicines: These are medicines that contain one or more medical devices as an integral part of the medicine.

Cell therapy-based medicinal products (CTMPs) are defined as medicinal products when there is more than minimal manipulation of the cellular component or where the intended use of the cells is different from their normal function in the body.

Much attention had been paid to the potential of novel stem cell- and tissue engineering-based therapies following a number of relevant scientific milestones and media news of potential new cures [2,3]. These therapies have become the focus of many biopharmaceutical developments, which face a number of major challenges in translating these scientific advances into Food and Drug Administration (FDA)/European Medicines Agency (EMA)-approved medical products. ATMPs, including cell therapy and tissue engineering products, are considered as medicines in the European Union [4].

ATMPs are at the forefront of scientific innovation in medicine; consequently, specific regulatory framework has been developed and implemented in Europe and in the United States. In this regard, the Regulation (EC) N° 1394/2007 on ATMPs was drafted and came into force in December 2008. The Regulation laid down specific rules concerning centralized authorization and pharmacovigilance of the ATMPs. This regulatory framework has a crucial influence in the development of such ATMPs. As a consequence, the teams involved in the ATMP development must take into account the FDA/EMA scientific and regulatory guidelines that provide a detailed description of the safety, efficacy, and quality issues for CTMPs [5,6]. As we can see in Box 1, cell therapy and tissue engineering products are very clearly defined by regulatory agencies.

Box 1

What are Cell Therapy and Tissue Engineering Products?

Cell therapies and tissue engineering products are considered as medicines when the following are true:

• Cell-based product:

• Substantial manipulation of cells or not intended to be used for the same essential function(s)

• Administered to human beings with a view to treating, preventing, or diagnosing a disease through the pharmacological, immunological, or metabolic action

• Tissue-engineered product:

• Substantial manipulation of tissues or not intended to be used for the same essential function(s)

• Engineered cells or tissues

• Administered to human beings with a view to regenerating, repairing, or replacing a human tissue

2. Key Pharmaceutical Factors to Consider in Early Development Stages

Several technical obstacles must be overcome during the stages of product conception and design, before cell and tissue engineering therapies move out from basic research laboratories to clinical phases of investigation. There are many challenges associated with characterizing and quantifying the raw materials, cells, reagents, and processes for the therapies. From a regulatory point of view, ATMPs must be safe and effective and also be produced following high-quality manufacturing processes that allow for on-time delivery of viable products. CTMPs developers must be able to respond to the following:

• Quality considerations: Define a manufacturing process that is able to consistently produce sterile and pyrogen-free drug products with defined identity, purity, and potency, and produce a strong foundation in product development and cell characterization (as it relates to therapeutic efficacy of cell-based drugs).

• Nonclinical considerations: Adequately evaluate different aspects including proof of concept, dosage, biodistribution, persistence, and safety (i.e., tumorogenicity, immune rejection). In vitro or in vivo models may provide information, hence the importance of using biologically relevant preclinical models of safety and efficacy. Understand and control the mechanism of action and use of reliable potency assays. Establish the pharmacodynamics and pharmacokinetics and dose-finding studies.

• Bioprocess considerations: What is required to create scalable and robust manufacturing processes [7] are considered. What are the basic unit operations: cell expansion, centrifugations. Economic cost of the cell production process should be carefully considered to avoid unrealistic approaches.

• Stability: Due to the living nature of ATMP, stability is one of the most challenging aspects. This aspect should be studied from the beginning. Long and noncomplex conditions of storage are desirable. The formulation and packaging strongly influence stability characteristics. Once the product has been totally developed, long-term stability programs should be performed.

• Product characterization: Develop potency tests [8]. To establish the activity of the product, adequate tests must be developed. These tests should mimic, as much as possible, the desired biological function to be developed by the ATMP inside the organism. After the development of the test, limitations such as economic or time restrictions due to the limited stability of the final product have to be evaluated.

• Packaging/administration considerations: A good product with complex packaging or administration system can be rejected by the clinicians due to intrinsic complexity of the surgery. Simple and secure packaging forms should be considered. For injectable drug products, prefilled injections are preferable.

The lack of drug development know-how and experience can lead to the definition of products that may not be feasible for clinical evaluation or future commercialization. A poor understanding of the drug product characteristics and ineffective process development can impair critical product characteristics and lay the foundation for clinical failure. In this regard, attention should be paid in the early stages of development to clearly define the characteristics with special consideration of the regulatory and clinical practitioners needs in mind (Table 2).

Table 2

Analysis of Potential for Errors and Recommendations in the Development of Cell-Based Therapeutics

CBMP  =  cell-based medicinal product; CRO  =  contract research organization; FTO  =  freedom to operate.

Adapted from Vives et al. [13].

3. TPP: Beginning with the End in Mind

The use of a systematic approach such as the target product profile (TPP) can facilitate the right regulatory and business approaches, determine market segments, and create an understanding of the competition and associated pricing strategies. A TPP is a key strategic document that summarizes features of an intended commercial therapeutic product. The definition of a TPP according to the target-disease health requirements and user needs should drive the design of other fundamental aspects as the primary container-closure system, the stability requirements, or the logistic approach. This later point is critical because of the special features of cell therapy and tissue engineering products. This reflection and the effort to understand the problem result in improved provider/patient convenience and regulatory compliance, as well as product differentiation. Further, the use of TPP will enable achieving an integrated approach to product and process development that can lead to clinical and commercial success [9].

The TPP is an organized list, developed and agreed upon from multiple stakeholder perspectives, which prioritizes the key features and attributes of the intended end product (the marketed drug). The TPP is a dynamic, evolving, written document, and is a focal point of reference for the project. It covers at least the following areas:

• Strategic context

• Medical and commercial requirements and priorities

Box 2

TPP basic features for cell-based medicinal products

Features of a TPP

• Indications and use

• Productive process

• Dosage and administration

• Product characteristics

• Contraindications

• Conservation and stability

• Industrial protection

• Regulatory strategy

• Patient requirements

• Technical (research) and biological features

• Technical (development) requirements and feasibility

• Desired versus minimally acceptable features

The TPP is a valuable tool to organize all relevant information from multiple perspectives (i.e., medical, market, production, regulatory). This living document can be used to help us get a right relationship between development and attributes of a desired ATM drug (see Box 2).

4. Stages of Drug Development

The length of the cell therapy pharmaceutical product development from discovery to market might take several years with extensive financial and scientific risks (Figure 1). The process is long and uncertain, and in addition, as soon as market arrival, the product developed must also compete with existing treatments. Taking into account this complex scenario, multiple aspects complementary to product conception, design, and development should be considered to increase the possibility of market arrival and commercial success.

Any drug development process must proceed through several stages, as detailed next:

• Discovery: Once the TPP is defined, the development process begins with the performance of pending aspects related to basic research or literature review, in which the regenerative basis of diseases are targeted, studied, and then therapies are proposed. A key milestone of this development stage is the understanding and validation of the proof-of-principle. This involves obtaining strong in vitro and animal data. When the therapeutic approach has been developed and proof-of-principle validated, intellectual property issues must be addressed to ensure freedom to operate in the area of interest. This is a critical step to attract or maintain investors and to prevent ideas from being appropriated by a third party. Without a patent, investors will not feel their high-risk investment is safe from others simply copying the process or product once it is approved. Patents are most commonly used for cell and tissue therapy and can protect an innovation for 20  years.

Figure 1  Development pipeline.

Flowchart depicting the phases of the development of a cell-based therapeutic up to the Phase I/IIa clinical trial. IMPD  =  investigational medicinal product dossier; IND  =  investigational new drug; POP  =  proof-of-principle. Adapted from Vives et al. [13].

• Preclinical studies: The objective of preclinical studies is to test the safety of the products and to gain insight into the working mechanisms of the cell therapies. These studies should be done before the submission of the Common Technical Document (CTD) to EMA, and complementary data can be obtained during clinical trials. Nonclinical evidence on the proof-of-principle and safety of the stem cell-based product in a relevant animal model is expected.

• Clinical trials: Clinical trials should be designed to demonstrate safety and efficacy as well as evidence to substantiate the mode of action identified during the clinical trial [10]. Briefly, once the EMA approves a drug for clinical trials, Phase I is performed to check the safety and concept proof of the drug. If a drug passes Phase I testing (or Phase I/IIa, for most ATMP developments) and is considered safe for humans, the drug product is then tested on patients in Phase II clinical trials. Phase II studies involve a higher number of patients divided into subgroups to test different doses. The data obtained in Phase II clinical trials are used for the primary purpose of designing optimal Phase III clinical trials. Phase III trials will be used as a basis for obtaining statistically significant data to prove the effectiveness and to warrant the safety of the drug. This development stage is known as the pivotal trials because the data generated at this stage are used to obtain regulatory approval.

• Approval and post-marketing testing: Finally, if a drug passes Phase III clinical studies and the new drug application (NDA) is approved, the drug can be marketed for sale to the public.

At every stage of drug development (discovery, nonclinical, clinical, and commercialization), specific quality and regulatory frameworks must be applied: good laboratory practices, good manufacturing practices, and good clinical practices. Therefore, companies conducting ATMP developments must have a quality system (QS) with the appropriate Good Scientific Practice regulations (GxP) in place, which are inspected and certified by regulatory authorities. The QS must guarantee various aspects:

• Quality management

• Quality assurance

• Risk management tools

• Continuous improvement

Implementing and maintaining efficient QS can represent a complex task and involves up-front costs. In this regard, quality cannot be an afterthought. Implementing an effective quality system should be in place at the