Drug Delivery Trends: Volume 3: Expectations and Realities of Multifunctional Drug Delivery Systems [1 ed.] 0128178701, 9780128178706

Table of contents :
Drug Delivery Trends
Copyright
Contributors
Preface
1 - Bioactive hybrid nanowires: a new in trend for site-specific drug delivery and targeting
1. Introduction
2. Types of nanowires
3. Production methods
3.1 Top-down method
3.2 Bottom-up method
4. Applications of nanowires
4.1 Nanowires in bioanalytical chemistry
4.2 Nanowires as biosensors in medical diagnosis
4.3 Nanowires for delivery of chemotherapeutics
5. Conclusions
Acknowledgments
References
2 - Opportunities and challenges of 3D-printed pharmaceutical dosage forms
1. Introduction
2. Materials
2.1 Aliphatic polyesters
2.2 Cellulose ethers and esters
2.3 Acrylic polymers
2.4 Vinyl polymers
2.4.1 Novel polymers in the market
2.4.2 Additives
3. Technology details
3.1 Vat photopolymerization
3.1.1 Stereolithography apparatus
3.1.2 Digital light processing
3.1.3 Continuous liquid interface production
3.2 Powder bed fusion processes
3.2.1 Selective laser sintering process/laser sintering process
3.2.2 Powder binding technology
3.3 3D material extrusion—fused filament fabrication
3.3.1 Postprocessing
4. Regulatory and quality considerations
5. Pharmaceutical applications for drug delivery
5.1 Tunable release technologies
5.2 Paste/gel extrusion-based technologies
6. Conclusions
References
Further reading
3 - Marketing authorization and licensing of medicinal products in EU: Regulatory aspects
1. Introduction
2. European Union legal framework, hierarchy, and committees
2.1 The European Union
2.2 The European commission [1]
2.3 Departments and agencies [2]
2.4 Consumers, health, agriculture and food executive agency [3]
2.5 Health and food safety department [4]
2.6 European medicines agency [5]
2.6.1 Committee for medicinal products for human use [6]
2.6.1.1 Role
2.6.2 Pharmacovigilance risk assessment committee [7]
2.6.2.1 Role
2.6.3 Committee for medicinal products for veterinary use [8]
2.6.3.1 Role
2.6.3.1.1 Assessments
2.6.4 Committee for Orphan Medicinal Products [9]
2.6.4.1 Role
2.6.5 Committee on herbal medicinal products [10]
2.6.5.1 Role
2.6.6 Committee for advanced therapies [11]
2.6.6.1 Role
2.6.7 Paediatric committee [12]
2.6.7.1 Role
2.7 Coordination groups
2.7.1 Coordination group for mutual recognition and decentralised procedures—human [13]
2.7.2 Composition
2.7.3 Meetings and reports
2.7.4 Safety referrals
3. Legal framework for licensing medicines for human use in the EU
3.1 Introduction
3.2 Directive 2001/83/EC [15]
3.2.1 Article 6
3.2.2 Article 8(3)(i)
3.2.3 Article 10.1
3.2.4 Article 10.3
3.2.5 Article 10a
3.2.6 Article 10b
3.2.7 Article 10c
3.3 Regulation (EC) No. 726/2004 [16]
3.4 EudraLex [17]
3.5 Volume 2A—Chapter 1
3.5.1 Marketing authorization
3.5.2 National authorization
3.5.3 Union authorizations
3.5.4 Notion of “global marketing authorization”
3.5.5 Validity of the marketing authorization
3.5.5.1 Renewal
3.5.5.2 Cessation of the marketing authorization if the medicinal product is not marketed
3.5.6 Naming of a medicinal product
3.5.7 Transparency
3.5.8 Multiple application
3.5.8.1 Centralized application
3.5.8.2 Mutual recognition and decentralized procedures
3.5.8.3 Concept of “applicant and marketing authorization holder”
3.6 Marketing authorization procedures
3.6.1 Centralized procedure
3.6.2 Decentralized procedure and mutual recognition procedure
3.6.3 Decentralized procedure
3.6.4 Mutual recognition procedure
3.6.5 Independent national procedures
3.7 Paediatric requirements for medicinal products
3.8 Union referrals
3.8.1 Referral according to Article 29 of Directive 2001/83/EC
3.8.2 Referral in accordance with Article 30(1) of Directive 2001/83/EC
3.8.3 Referral in accordance with Article 30(2) of Directive 2001/83/EC
3.8.4 Referral in accordance with Article 31 of Directive 2001/83/EC
3.8.5 Referral in accordance with Article 107i of directive 2001/83/EC
3.9 Application types
3.9.1 Applications according to Article 8(3) of Directive 2001/83/EC
3.9.2 Applications according to Article 10 of Directive 2001/83/EC
3.9.2.1 Reference medicinal product
3.9.2.2 European reference medicinal product
3.9.2.3 Particularities for application according to Article 10
3.9.2.4 Applications in accordance with paragraph 3 of Article 10 (“hybrid medicinal product”)
3.9.2.5 Applications according to Article 10a of Directive 2001/83/EC
3.9.2.6 Well-established medicinal use
3.9.2.7 Documentation
3.9.2.8 Applications according to Article 10b of Directive 2001/83/EEC
3.9.2.9 Applications according to Article 10c of Directive 2001/83 /EC
3.10 Data exclusivity and market protection
3.10.1 Protection periods and global marketing authorization
3.10.1.1 Extension of the 10-year period in Article 10(1) in the case of new therapeutic indications
3.10.1.2 One-year period of protection for new indications of well-established substances
3.10.1.3 One-year period of protection for data supporting a change of classification
3.11 Variations and extensions
3.11.1 Variations
3.11.1.1 Minor variations of Type IA
3.11.1.2 Minor variations of Type IB
3.11.1.3 Major variations of Type II
3.12 Extensions
4. Conclusion
Acknowledgments
References
4 - Clinical considerations on micro- and nanodrug delivery systems
1. Introduction
2. Outline of drug development
3. Micro- and nanoparticles in drug delivery
3.1 Nonvesicular drug delivery systems
3.1.1 Microemulsions
3.1.2 Nanoemulsions
3.1.3 SLNs
3.1.4 NLCs
3.1.5 Polymeric nanoparticles
3.1.6 Polymeric microparticles
3.2 Vesicular drug delivery systems
3.2.1 Liposomes
3.2.2 Transfersomes
3.2.3 Ethosomes
3.2.4 Niosomes
4. Applications of micro- and nanoparticles
4.1 Cancer therapy
4.2 Nanoparticles as diagnostic agents
4.3 Treatment of acquired immunodeficiency syndrome
4.4 Delivery of nutraceuticals
5. Regulatory aspects of nanotechnology-based products
6. Conclusion
References
5 - Nanoparticulate treatments for oral delivery
1. Introduction
2. Need for nanotechnology in oral solid dosage forms
2.1 Bioavailability enhancement
2.2 Targeting specific regions of the physiology
2.3 Improved physiological stability
2.4 Sustained or controlled release effect
3. Formulation perspectives
3.1 Solid lipid nanoparticles (SLNs)
3.1.1 Hot melt extrusion
3.1.2 Solvent emulsification/evaporation
3.1.3 Hot/cold homogenization [33,40]
3.1.4 Microemulsion [41]
3.1.5 Supercritical fluid
3.2 Polymeric nanoparticles
3.3 Nanomicelles
3.4 Nanosuspensions
4. Challenges
5. Conclusions
Abbreviations
References
6 - Pharmaceutical mini-tablets: a revived trend
1. Introduction
2. Advantages of mini-tablets
2.1 Dosages
2.2 Customized delivery
2.3 Improving patient compliance
2.4 Combination therapy
2.5 Dose range finding
2.6 Disintegration times
2.7 Product design
2.8 Caregivers
2.9 Excipients
2.10 Marketed mini-tablets
2.11 Packaging
3. Manufacturing
4. Types of mini-tablets
4.1 Pediatric mini-tablets
4.2 Gastroretentive mini-tablets
4.3 Orally disintegrating mini-tablets
4.4 Ocular mini-tablets
4.5 Bioadhesive vaginal mini-tablets
4.6 pH-responsive mini-tablets
4.7 Biphasic mini-tablets
5. Methods of manufacturing mini-tablets
5.1 Direct compression
5.2 Dry granulation
5.3 Wet granulation
5.4 Hot melt extrusion
6. Challenges in the manufacturing of mini-tablets
7. Coating of mini-tablets
8. Fluidized-bed coating of mini-tablets
9. Pan coating of mini-tablets
10. Novel coating technology for mini-tablets
11. Packaging of mini-tablets
12. Encapsulation of mini-tablets into capsules
13. Unit-dose packing of mini-tablets into sachets
14. Conclusion
References
7 - Liquid crystalline drug delivery systems
1. Introduction
2. Preparation of LC systems
3. Characterization of liquid crystalline phases
4. Applications of liquid crystalline systems
5. Conclusion
Acknowledgments
References
8 - Amorphous drug stabilization using mesoporous materials
1. Background
2. Introduction
3. Mesoporous materials
4. Structural characterization of mesoporous materials
5. Mesoporous materials in drug delivery
6. Different forms of the loaded drug: monolayer versus pore filling
7. Drug loading techniques
7.1 Solvent-based loading
7.2 Solvent-free loading
8. Performance of drug-loaded mesoporous materials
8.1 Physical stability
8.2 Dissolution and in vivo performance
9. Conclusion
References
9. “Quality” of pharmaceutical products for human use—underlying concepts and required practices
1. Introduction
2. In vivo testing (clinical studies)
2.1 Bioavailability assessments
2.1.1 Permeability, absorption, and bioavailability
2.1.2 A typical bioavailability assessment protocol
2.2 Bioequivalence assessments
3. In vitro assessments or drug dissolution testing
4. Linking in vitro dissolution results to in vivo characteristics/IVIVC
4.1 Deconvolution and convolution techniques and applications
5. Regulatory standards and requirements
6. Limitations and deficiencies of the current practices and requirements for quality assessment
6.1 Drug product versus drug assessment
6.2 In vivo assessments
6.3 In vitro and in vivo correlation
6.4 In vitro testing
6.5 Use of computational modeling for linking in vitro and in vivo characteristics
7. Future outlook
7.1 Defining the “quality” of products and drugs
7.2 Lack of clarity of regulatory practices
7.3 Choice of drug dissolution apparatuses and experimental conditions
7.4 Drug dissolution testing using simple and common experimental conditions
7.5 Practices and requirements of predicting plasma drug levels from in vitro drug dissolution results
8. Conclusions
References
10 - Optimizing intraperitoneal drug delivery: pressurized intraperitoneal aerosol chemotherapy (PIPAC)
1. Introduction
1.1 Poor vascularization of the peritoneum
1.2 Increased interstitial intratumoral fluid pressure
2. Optimizing drug therapy in peritoneal metastasis
3. Limitations of intraperitoneal chemotherapy
4. Understanding drug uptake into peritoneal nodes
5. Pharmacokinetics aspects of intraperitoneal chemotherapy
6. Pharmacodynamic aspects in intraperitoneal chemotherapy
7. Pharmacological interventions to increase drug uptake
8. Role of formulation
9. Physical interventions to improve drug uptake
10. Specifications for an ideal intraperitoneal drug delivery system
11. Peritoneal aerosol medicine
12. Pressurized intraperitoneal aerosol chemotherapy
13. Electrostatic precipitation pressurized intraperitoneal aerosol chemotherapy
14. Chemotherapeutic agents used as PIPAC
14.1 Oxaliplatin
14.2 Cisplatin and doxorubicin
14.3 Nab-paclitaxel
14.4 Caelyx
14.5 Irinotecan
15. Preclinical studies
15.1 Paclitaxel
15.2 siDNA
15.3 siRNA
16. Combination of PIPAC with systemic chemotherapy
17. In silico modeling
18. Conclusion and outlook
References
11 - Upscaling and GMP production of pharmaceutical drug delivery systems
1. Scalability
1.1 Top-down methods
1.1.1 Milling
1.1.2 High-pressure homogenization
1.2 Bottom-up methods
1.2.1 Nanoprecipitation
1.2.2 Salting out
1.2.3 Supercritical fluid technology
2. Sustainability
2.1 Downstreaming for parenteral formulations
2.1.1 Purification
2.1.2 Sterilization
2.1.3 Freeze drying
2.2 Downstreaming to solid dosage forms
2.2.1 Granulation
2.2.2 Spray drying
3. GMP compliance
4. Conclusion
References
Index
A
B
C
D
E
F
G
H
I
L
M
N
O
P
Q
R
S
T
U
V
W
Z

Citation preview

DRUG DELIVERY TRENDS EXPECTATIONS AND REALITIES OF MULTIFUNCTIONAL DRUG DELIVERY SYSTEMS VOLUME 3 Edited by

RANJITA SHEGOKAR, PhD Capnomed GmbH, Zimmern, Germany

Elsevier Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States Copyright © 2020 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN: 978-0-12-817870-6 For information on all Elsevier publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Andre Gerhard Wolff Acquisitions Editor: Erin Hill-Parks Editorial Project Manager: Pat Gonzalez Production Project Manager: Punithavathy Govindaradjane Cover Designer: Mark Rogers Typeset by TNQ Technologies

Contributors Salvana Costa Universidade Tiradentes (UNIT), Aracaju, Sergipe, Brazil J.

Saeed A. Qureshi ON, Canada

Pharmacomechanics, Ottawa,

Vivek Ranjan Sinha University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India

Dias-Ferreira Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), P
olo das Ciências da Sa
ude, Azinhaga de Santa Comba, Coimbra, Portugal

M.A. Reymond National Center for Pleura and Peritoneum, University of T€ ubingen, T€ ubingen, Germany

A.R. Fernandes Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), P
olo das Ciências da Sa
ude, Azinhaga de Santa Comba, Coimbra, Portugal

Patrícia Severino Universidade Tiradentes (UNIT), Aracaju, Sergipe, Brazil; Instituto de Tecnologia e Pesquisa (ITP), Aracaju, Sergipe, Brazil

Rohit C. Ghan Aurobindo Pharmaceuticals USA Inc., Dayton, NJ, United States

Ranjita Shegokar Capnomed GmbH, Zimmern, Germany

Randeep Kaur University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India

A.A.M. Shimojo Department of Materials Engineering and Bioprocesses, School of Chemical Engineering, State University of Campinas (UNICAMP), Cidade Universit
aria Zeferino Vaz e Bar~ ao Geraldo, Campinas, S~ ao Paulo, Brazil

Matthias M. Knopp Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark

A.M. Silva Department of Biology and Environment, School of Life and Environmental Sciences, University of Tr
as-os-Montes and Alto Douro, Vila Real, Portugal; Centre for the Research and Technology of Agro-Environmental and Biological Sciences, University of Tr
as-os-Montes and Alto Douro, Vila Real, Portugal

A. K€ onigsrainer National Center for Pleura and Peritoneum, University of T€ ubingen, T€ ubingen, Germany Korbinian L€ obmann Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark Conrado Marques Universidade Federal de Sergipe (UFS), Campus Lagarto, Departamento de Medicina, Sergipe, Largarto, Brazil

Eliana B. Souto Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), P
olo das Ciências da Sa
ude, Azinhaga de Santa Comba, Coimbra, Portugal; CEB e Centre of Biological Engineering, University of Minho, Campus de Gualtar, Braga, Portugal

Muhaned Al-Hindawi OnTarget Pharma Consultancy Limited, New Malden, Surrey, United Kingdom Luciana Nalone Universidade Tiradentes (UNIT), Aracaju, Sergipe, Brazil; Instituto de Tecnologia e Pesquisa (ITP), Aracaju, Sergipe, Brazil Adam Procopio United States

M.C. Teixeira Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), P
olo das Ciências da Sa
ude, Azinhaga de Santa Comba, Coimbra, Portugal

Merck & Co., Inc., Kenilworth, NJ,

vii

viii

Contributors

Divya Tewari Noramco Inc., Wilmington, DE, United States

€ Akif Emre T€ ureli MJR PharmJet GmbH, Uberherrn, Saarland, Germany

Pramil Tiwari Department of Pharmacy Practice, National Institute of Pharmaceutical Education & Research (NIPER), S.A.S. Nagar, Punjab, India

Danillo F.M.C. Veloso Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark

Nazende G€ unday T€ ureli MJR PharmJet GmbH, € Uberherrn, Saarland, Germany

Venkat Tumuluri Novartis Healthcare Pvt. Ltd., Hyderbad, India

Preface

4. establish collaborations between academic scientists, and industrial and clinical researchers.

The book series titled Expectations and Realities of Multifunctional Drug Delivery Systems covers several important topics on drug-delivery systems, regulatory requirements, clinical studies, intellectual properties trends, new advances, manufacturing challenges, etc. written by leading industry and academic experts. Overall, the chapters published in this series reflect the broadness of nanopharmaceuticals, microparticles, other drug carriers, and the importance of respective quality, regulatory, clinical, GMP scale-up, and regulatory registration aspects. This series is destined to fill the knowledge gap through information sharing and with organized research compilation between diverse areas of pharma, medicine, clinical, regulatory practices, and academics. Expectations and Realities of Multifunctional Drug Delivery Systems is divided into four volumes: Volume 1: Nanopharmaceuticals Volume 2: Delivery of Drugs Volume 3: Drug Delivery Trends Volume 4: Drug Delivery Aspects

Innovative cutting-edge developments in micro-nanotechnology offer new ways of preventing and treating diseases like cancer, malaria, HIV/AIDS, tuberculosis, and many more. The applications of micro-nanoparticles in drug delivery, diagnostics, and imaging are vast. Hence, Volume 3: Drug Delivery Trends in the book series mainly reviews advances in drug delivery areas via targeted therapy with improved drug efficiency at a lower dose, transportation of the drug across physiological barriers, as well as reduced drug-related toxicity. The contribution by Fernandes et al. (Chapter 1) discusses new trends in drug delivery areas via bioactive hybrid nanowires. Nanowires offer multifunctionality and the prospect of biofunctionalization, thereby reducing toxicity and side effects. This synergistic approach overcomes the challenges associated with conventional nanomedicines and exhibits better performance. The authors review the potential of nanowires in this chapter. The chapter by Procopio and Tewari (Chapter 2) highlights another industry trenddi.e., 3D printing. This is a fascinating topic recently adopted by industry. The Food and Drug Administration has already approved the first product: Spritam (levetiracetam), a 3D printed tablet (Aprecia Pharmaceuticals). A thorough overview of material requirements, types of

The specific objectives of this book series are to: 1. provide a platform to discuss opportunities and challenges in development of nano medicine and other drug-delivery systems; 2. discuss current and future market trends; 3. facilitate insight sharing within various areas of expertise; and

ix

x

Preface

polymer, available 3D printing techniques, and regulatory aspects is provided. Finally, the authors present case studies from industry on tunable release technology and paste gel extrusion in tableting. The contribution by Al-Hindawi (Chapter 3) describes marketing authorization and licensing of medicinal products in the European Union. The main aim of this chapter is to provide readers with a generalized overview of the steps and criteria while applying licenses in the European Union. The author also highlights various directives, extension requests, protection periods, and legal requirements guidance to industry and researchers. On the other hand, preclinical understanding is key to proposing products for particular indications. The chapter by Tiwari et al. (Chapter 4) reviews preclinical considerations on microand nanodrug delivery, which will lead to the proper positioning of products for market authorization. The work by Ghan (Chapter 5) is aimed at discussing synergistic delivery of nanoparticles using traditional approaches like tableting or other forms. The author reviews various nanoparticulate treatments for oral delivery to improve bioavailability, target specific regions in the gastrointestinal tract, improve physiological stability in the gut environment, and modulate release when needed. Drug delivery systems like solid lipid nanoparticles, polymeric nanoparticles, nanomicelles, and nanosuspension are also reviewed. The chapter by Tumuluri (Chapter 6) highlights opportunities and challenges in formulating minitablets. This is another trend in oral drug delivery systems besides nano-oral and 3D printed dosage forms. The author describes in detail technological potential, industrial advantages, technological availability, and the limitations of minitablets. The topic presented by Nalone et al. (Chapter 7) describes the potential of liquid crystalline systems in drug delivery. This chapter

discusses in detail the mechanism of formation of liquid crystalline systems, types of structure formed, factors affecting formation of liquid crystalline systems, compositions, advantages, and limitations of these forms of drug delivery systems. The chapter by Veloso et al. (Chapter 8) reviews opportunities and challenges in amorphous drug stabilization using mesoporous materials. The team of authors highlights key points like the role of mesoporous materials, structural characterizations of such systems, physical forms of drug loading, and physical performance of mesoporous particles. Mesoporous particles have huge potential in pharmaceuticals as a drug delivery system, in cosmetics, in nutraceuticals, and in fast-moving consumer goods (detergent, oral care), and is a highly explored trend in the market. Quality is an important aspect in regulatory which makes sure patients receive “quality” products. Newer trends in pharmaceuticals like nanomedicines, drug device combinations, nanoparticulate-based tablets, etc. require special techniques and an understanding of quality. The chapter by Qureshi (Chapter 9) asks questions like “what is quality?”, “do we evaluate quality as per a regulatory definition?”, and “is there a need to change the definition of quality when a product is altered?” The main theme of this chapter is to underline basic concepts of “quality” and discuss them with regard to current practices. The author provides his views on further modifications of current testing methodologies to assure “real quality.” The work by Reymond and K€ onigsrainer (Chapter 10) is aimed at discussing the potential of pressurized intraperitoneal aerosol chemotherapy (PIPAC). The authors review various chemotherapeutic systems currently used in vitro/ex vivo models and the success of clinical trials to date. This generalized overview of PIPAC technology provides readers with updates from another innovative trend in medical practice.

Preface

The last contribution by T€ ureli and T€ ureli (Chapter 11) describes industrial challenges of upscaling and good manufacturing practice in the production of pharmaceutical drug delivery systems. The authors highlight the current regulatory status of approved nanomedicines and manufacturing limitations and initiatives. In summary, I am sure this book volume and the complete book series will provide you great

xi

insights in areas of micro-nanomedicines, drug delivery sciences, new trends, and regulatory aspects. All the efforts of experts, scientists, and authors are highly acknowledged for sharing their knowledge, ideas, and insights about the topic. Ranjita Shegokar, PhD Editor

C H A P T E R

1 Bioactive hybrid nanowires: a new in trend for site-specific drug delivery and targeting A.R. Fernandes1, J. Dias-Ferreira1, M.C. Teixeira1, A.A.M. Shimojo2, Patrícia Severino3,4, A.M. Silva5,6, Ranjita Shegokar7, Eliana B. Souto1,8 1

Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), P
olo das Ci^encias da Sa
ude, Azinhaga de Santa Comba, Coimbra, Portugal; 2Department of Materials Engineering and Bioprocesses, School of Chemical Engineering, State University of Campinas (UNICAMP), Cidade Universit
aria Zeferino Vaz e Bar~ao Geraldo, Campinas, S~ao Paulo, Brazil; 3 Universidade Tiradentes (UNIT), Aracaju, Sergipe, Brazil; 4Instituto de Tecnologia e Pesquisa (ITP), Aracaju, Sergipe, Brazil; 5Department of Biology and Environment, School of Life and Environmental Sciences, University of Tr
as-os-Montes and Alto Douro, Vila Real, Portugal; 6Centre for the Research and Technology of Agro-Environmental and Biological Sciences, University of Tr
as-os-Montes and Alto Douro, Vila Real, Portugal; 7Capnomed GmbH, Zimmern, Germany; 8CEB e Centre of Biological Engineering, University of Minho, Campus de Gualtar, Braga, Portugal

1. Introduction

can be terminated at temperatures ranging from 41 to 46
C or below 47
C for at least 20e60 min [2,3]. Hyperthermia is therefore used locally to prevent disease by exposing the whole body to high temperatures to overcome adverse side effects and to increase treatment efficiency [4]. The introduction of magnetic nanoparticles in cancer hyperthermia has been developed and grown significantly during the last decade.

Hyperthermia (“hyper” and “therme”, meaning “rise” and “heat”) is a therapeutic approach to cancer treatment. Some researchers have related that a sarcoma disappeared after a very high fever. This finding is due to the reaction of immune systems with bacterial infection [1]. Cancer cells are recognized as being vulnerable to high temperatures. The growth of these cells

Drug Delivery Trends https://doi.org/10.1016/B978-0-12-817870-6.00001-8

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© 2020 Elsevier Inc. All rights reserved.

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1. Bioactive hybrid nanowires: a new in trend for site-specific drug delivery and targeting

The special features of these particles are related to their capacity to efficiently accumulate at the tumor cells through the increased permeability of the tumor vessels and by cancer-specific binding agents, making the treatment more selective and effective [5]. The application of an alternating magnetic field (AMF) with the introduction of magnetic nanoparticles generates local heat in the tissues that contain these nanoparticles due to magnetic relaxation and hysteresis loss [6]. Particle characteristics such as size distribution, shape, crystal structure, particle magnetic anisotropy and its temperature dependence on magnetization, fluid viscosity, amplitude and frequency of the AMF directly affect the generation of heat, which in turn depends on the absorption efficiency of the magnetic particles [1,7]. A significant number of magnetic nanoparticles have been studied over the last few decades. Examples of well-known hyperthermic agents include iron oxide-based nanomaterials such as magnetite (Fe3O4) and maghemite (gFe2O), which continue attracting attention due to their lack of toxicity and excellent biocompatibility [8]. Ferrite nanoparticles (XFe2O4, where X can be Co, Mn, Ni, Li, or mixes of these metals), metallic nanoparticles, such as Mn, Co, Ni, Zn, Gd, Mg, and their oxides, or metal alloys (FeCo, CoPd, FePt, NiPd, NiPt, NiCu) have also been studied as possible candidates for hyperthermia treatments [9e11]. There are new designs of magnetic nanomaterials based on a core/shell approach that have started to gain prominence due to their versatility to tailor properties of both core and shell and to offer multifunctionality, such as core protection, biofunctionalization platform, toxicity reduction, and increase in biocompatibility. Examples of these particles are gold- or silica-coated ferromagnetic particles [12]. Magnetic nanoparticles also hold great promise for drug delivery by heating the tissues. The drug can be released using two strategies. In the first approach, the drug molecules are attached to the particles through a linker, which breaks with the heat generated by

the presence of AMF, with the consequent release of the drug. In the second approach, the release of drugs takes place from a polymeric matrix with magnetic material [5,13]. The heat created by the magnetic field produces crevices or cracks inside the polymeric matrix, which releases the encapsulated drugs [5]. Nanowires, nanowhiskers, nanofibers, nanotubes, and other one-dimensional nanostructures have demonstrated huge abilities for improving the electrical, optical, thermal, and mechanical properties of a broad range of functional materials and composites [14]. These enhancements substantially exceed those offered by micro- or nanosized particles. Most of the methods used for their synthesis are relatively expensive and difficult to scale up [15]. The underlying principles for the synthesis of one-dimensional materials offer significant challenges in the control of diameter, structure, and composition in the axial and radial coordinates, which are essential for the synthesis of materials with designed and tunable functionality [16]. Nanowires, besides their magnetic performance, also have aso an interest in developing intrinsic mobility triggered by a photochemical reaction. Examples of applications of magnetic segmented nanowires are: 1. Magnetic alignment and wireless manipulation (Au/polypyrrole/Ni) [17] 2. Magnetic field sensors and spintronic nanodevices (Co/Cu and FeCoNi/Cu) [18] 3. Photochemical conversion and hydrogen generation (Ag/ZnO) [19] 4. Detection of DNA molecules (CdTe/Au/ CdTe) [20] 5. Magnetic control of biomolecule desorption (FeCo/Cu) [21] 6. Exchange-coupled patterned media (Ni/ CoPt) [22] 7. Nanosensors (Au/Co) [23] 8. Catalytic activities (Pt/Ni) [24] 9. Higher oxygen reduction reaction activity (Co/Pt) [25,26] 10. Drug delivery

3

3. Production methods

Magnetic nanoparticles (including nanowires) are recognized as nanoparticles with unique physicochemical properties and are mostly different from those of conventional materials, specifically the electromagnetic properties. Magnetic nanoparticles show good magnetic orientation, small size, biodegradability, and reactive functional groups [27]. The biocompatibility of magnetic nanoparticles can be improved by combining them with a variety of functional molecules such as enzymes, antibodies, cells, DNA, or RNA. The coating of other materials such as polyethylene glycol (PEG), chitosan, lipids, and proteins with good biocompatibility can stabilize magnetic nanoparticles in physiological fluids and provide chemical functionality for additional modifications [28].

composed of alternating structures of ferromagnetic/ferromagnetic or ferromagnetic/nonmagnetic materials, such as Ni/Cu [33], Ni/Au [34], Co/Cu [35], NiFe/Cu [36], CoNi/Cu [37], FeCoNi/Cu [38], FeGa/Cu [39], Co/Pt [40], NiFe/Pt [41], and NiCoCu/Cu [42], among others.

3. Production methods The properties of many systems are basically dependent of the material type used in production; however, in the case of nanowires the material geometry is also important. Thus to produce and maximize all the properties of nanowires requires reliable and controlled syntheses. The synthesis methods can be grouped into two categories: (1) top-down and (2) bottom-up synthesis.

2. Types of nanowires In the last few years, magnetic hybrid nanowires have been intensively studied for many applications, such as optics and medicine. There are two types of morphologies in hybrid nanowires: 1. Radial structures (core/shell type); and 2. Axial structures (segmented or layered type). The nanowires that present a core/shell structure explain many physical characteristics in the magnetism of the nanoparticles. The hard/soft core/shell nanoparticles have been studied and reveal interesting magnetic properties, i.e., reversible tuning of the blocking temperature [29], improved microwave absorption [30], optimized hyperthermia [31], and enhanced coercivity [32]. The magnetic segmented nanowires have multifunctional and structural advantages compared to their counterparts, singlecomponent nanowires. The literature reports that magnetic segmented nanowires are

3.1 Top-down method The most conventional top-down method in the fabrication of nanowires is lithography. Lithography is based on the deposition of a resistant material, for example, poly(methylmethacrylate), that has the function to act as a photographic film for the production of a pattern after exposure and development using a patterned mask. The resolution of this technique is dependent on the wavelength of light used in photolithography and sometimes is not suitable for small nanowires [43]. To obtain patterns with a higher resolution, normally electronbeam lithography is the method used, which does not use a mask and has direct-write exposure [44]. Thus nanowires can be obtained by etching the extraneous material from the wafer. Resistance can be applied directly because the etch mask can serve as the template for the deposition of a much more stable mask material, for example, gold. Material that can be used to

4

1. Bioactive hybrid nanowires: a new in trend for site-specific drug delivery and targeting

etch a pattern is, for example, potassium hydroxide (a wet chemical etchant) or another electrochemical etchant. With these materials it is possible to produce tapered cylindrical wires once the etching is underneath the mask [45]. One way to obtain cylindrical vertical wires is to change the wet chemical etch with a highly anisotropic deep reactive ion etch [46]. Nanosphere lithography is another approach that promises higher resolution by combining the self-assembly of a monolayer of nanospheres of polystyrene, for example, onto a substrate in a close-packed lattice [47]. The nanospheres serve as a model for the deposition of a metal or another material and are removed after deposition. Nanoscale patterns can be produced by mechanical transfer using nanoimprint lithography [48,49].

3.2 Bottom-up method In contrast to top-down techniques, bottomup synthesis offers the opportunity to control nanowire composition during growth. In this technique of the production of nanowires, the anisotropic growth of nanowires is normally done using nanoparticle catalysts and gas-phase precursors. The most used method of production is vapor/liquid/solid growth. In this method, gaseous precursors are used to obtain the desired nanowires and these precursors are dissolved into a liquid-metal catalyst, for example, in the case of silicon nanowires the precursor used is SiCl4. After the catalyst is supersaturated, solid nanowire crystallization from the liquid catalyst begins [50,51]. In this process, the metal should form a droplet in the liquid state that will serve as the catalyst. This droplet, in some cases, will melt at a lower temperature when compared to pure metal, due to its eutectic composition. In the case of the synthesis of binary or ternary compounds, which are metals with low melting points, the vapor/ liquid/solid system can be self-catalyzed [52]. The solution/liquid/solid method is another technique of nanowire production similar to

the vapor/liquid/solid method; however, in this case nanowire precursors are dissolved in a high-boiling liquid and the catalysts are suspended in this liquid [53]. Substrates, such as anodic aluminum oxide, can be used as template solution for nanowire growth, using electrochemical deposition and after filling the channels in the template [54]. Control of growth along the axes of nanowires is necessary for the introduction of surfactants capable of changing the surface energy of crystal facets, for example, hexadecyltrimethylammonium bromide. Anisotropy of nanowires is easy to achieve by the control of surface chemistry [55] (Tables 1.1 and 1.2 and Fig. 1.1).

4. Applications of nanowires Nanowire biosensors consist of typical fieldeffect transistor-based devices, made up of three electrodes that are very sensitive to the variation in the charge density that promotes changes in the electric field at the external surface of the nanowires [64]. Nanowires have a high surface-to-volume ratio and well-defined geometry; they have high sensitivity and short response time. These characteristics offer applications in biology and chemistry. Applications of nanowires can be categorized into two methodologies: electrical detection and optical detection [49].

4.1 Nanowires in bioanalytical chemistry One of the bioapplications of nanowires is biomolecule analysis. This application includes the study of mechanical cell lysis. Cellular lysis is a fundamental process in the study of intracellular components. There are a number of wellestablished methods that can analyze the cell components, such as chemical, electrical, and mechanical methods. In the case of chemical cell lysis many steps are necessary and it is an expensive process, consuming many reagents aimed at the purification of biomolecule samples. Another disadvantage is the high probability of the occurrence of harmful effects on

4. Applications of nanowires

5

FIGURE 1.1 Scanning electron microscopy images of CuS nanowires: (A) array; (B) copper oxide (CuO) nanotubes; (C) array; (D) fabrication using anodic aluminum oxide template. Image copied from Mu C, He J, Confined conversion of CuS nanowires to CuO nanotubes by annealing-induced diffusion in nanochannels. vol. 6. 2011. p. 150. Available via license: CC BY 2.0 (https:// creativecommons.org/licenses/by/2.0/). TABLE 1.1 Methods

Advantages and disadvantages of top-down and bottom-up methods [56e58].

Advantages

Top-down Easy to construct order arrays of nanowires. This order facilitates electrical contact with the nanowires and their integration into large-scale devices Compatibility of production methods with standard microelectronics industry processes. Easy scale-up

Disadvantages The applicability of the photolithography method decreases as the desired length scale diminishes, which requires the use of more advanced methods, for example, extreme ultraviolet lithography, electron-beam and scanning probe lithographies Nanowires formed by top-down methods frequently lack complex electronic characteristics. All the codifications after growth greatly increase the material cost of nanowire

Bottom-up Provides the opportunity for the control of the composition of nanowires during growth, which permits the production of complex superlattice structures

The major challenge of these methods is their integration into large-scale devices

microorganisms [65,66]. The solution to this problems is the use of electrical cell lysis, which is less harmful than the aforementioned method; however, it still an expensive method and has a

low throughput [67]. The ultimate discovery was the use of nanowires because of their small size (smaller than the cells) and the critical advantage is that the nanowire tip can penetrate and

6 TABLE 1.2

1. Bioactive hybrid nanowires: a new in trend for site-specific drug delivery and targeting

Drugs incorporated in nanowires.

Active pharmaceutical ingredient (API)

Type of system

Aim

Production methods

References

Paclitaxel

Cu nanowires

To target the spleen

Bottom up

[59]

Dexamethasone

Polypyrrole nanowires

For ulcerations, deep bone injuries, or tumors; avoids the side effects of systemic treatment with steroids or chemotherapy

Bottom up

[60]

Curcumin

Silver nanowires

Cancer treatment

Bottom up

[61]

Doxorubicin

Silver nanowires

Cancer treatment

Bottom up

[62]

Cerebrolysin

Hydrogen titanate nanowires

Reduction of brain edema

Top down

[63]

disrupt the function of cellular membranes [68]. Nanowires eliminate microorganisms in cells much faster than the previously described methods. In analytical and biological processes, the development of biomolecule separation and analysis is essential. In the separation of long DNA molecules, conventional gel electrophoresis has a disadvantage: it is necessary to analyze biomolecules for several hours. The combination of nanostructures produced by top-down approaches and microfluidic systems is usually proposed to overcome the problem. However, difficulty in their production using an electron-beam lithography process makes it a very expensive and sophisticated system [69,70]. On the other hand, nanostructures produced by bottom-up approaches offer easy fabrication and separation of biomolecules; however, size limitation causes difficulty in their development. To overcome all these problems, selfassembled nanowire structures of metal oxides have been investigated due to their rigidity and the possibility of reusability [49] (Table 1.3).

4.2 Nanowires as biosensors in medical diagnosis There are many challenges ahead that must be addressed before nanowires can be successfully

used for biomedical applications. Major challenges include 1. advanced techniques and easy methods (needed to increase the sensitivity of nanowirebased electrochemical cytosensors in signal amplification), 2. further research into nanowires to promote cell adhesion, sensitivity, and selectivity, 3. more specialized coatings to decrease nonspecific bonding, 4. protocols and further experiments to determine the exact nature of the nanotoxicity of nanowires and their constituents, 5. innovative solutions to reduce fabrication and running costs of nanowire-based micro/nanofluidic devices to make them economically viable, 6. with every emerging technology, standards to avoid doubts about the lack of reproducibility, repeatability, and compatibility across platforms and laboratories, and 7. an opportunity for further advances and developments of cytosensing devices based on electrochemical methods [73]. Circulating tumor cells play an essential role in cancer metastasis, and knowledge of their presence in blood samples of cancer patients is needed to understand more about the type of cancer. Hosokawa et al. have shown an array

7

4. Applications of nanowires

TABLE 1.3

Mechanical cell lysis

Biomolecule separation and filtration

Nanowires in bioanalytical analyses. Nanowire type

Production method

Results

References

ZnO nanowires (diameter: 100 nm) on the surface of a pillar array in a microchannel

Method of lowtemperature hydrothermal reaction

Higher extraction efficiency for nucleic acids and proteins than using chemical cell lysis methods

[71]

ZnO nanowires were Method of lowsynthesized on the Si temperature membrane (average hydrothermal reaction pore diameter: 75 nm)

Easy and rapid mechanical cell lysis Higher extraction efficiency for proteins and nucleic acids than that obtained for commercially available kits

[72]

SnO2 nanowires produced into fused silica microchannels

Nanowire structure controlled the pore [49] size (20e400 nm) by varying the number of nanowire growth times Highly dense nanowires, used as a molecular filter, could provide high-throughput filtration of DNA molecules

Photolithography process and vapor/ liquid/solid technique

of microcavities to perform size-selective capture of circulating tumor cells [74]. Another study reported that a herringbone chip captured and isolated clusters of circulating tumor cells from the patient’s blood, which had a capture efficiency of more than 80% [75]. Tseng et al. developed silicon nanowires, which they called a NanoVelcro chip, to capture and release circulating tumor cells from blood samples with high selectivity [76,77]. Si nanowires were produced based on substrates by a standard photolithography and chemical wet etching process, and they were then bonded to a chaotic mixture of microfluidic channels to fabricate the NanoVelcro chip. This procedure of surface modification with cell surface markers of anti-EpCAM increased the capturing efficiency of circulating tumor cells or of anti-CD45-depleted white blood cells on the nanowires [78,79]. The NanoVelcro chip with nanowires has been developed for singlecirculating tumor cell isolation by depositing thermoresponsive polymer brushes, poly(N-isopropylacrylamide), on silicon nanowires [78]. NanoVelcro chips are promising tools in

diagnosis, because they capture and purify circulating tumor cells rapidly prior to circulating tumor cell molecular analysis [49,76]. A silicon nanowire-based electrical cell impedance sensor has been developed for the detection of cancerous cultured living lung cells by monitoring their spreading state at which the cells stretched and became extended on nanowires [80]. The diagnosis was carried out by penetration into the extended membrane of malignant cells with respect to healthy cells. Silicon nanowire biosensors have advantages in molecular detection because of their high sensitivity and fast response. A polycrystalline silicon nanowire field-effect transistor device was developed to achieve specific and ultrasensitive detection of microRNAs without labeling and amplification, showing that the diagnostic and prognostic value of microRNAs in a variety of diseases is promising. Thus the polysilicon nanowire biosensor device is promising for microRNA detection [81]. In short, semiconductor nanowires are emerging as promising biosensors enabling

8 TABLE 1.4

1. Bioactive hybrid nanowires: a new in trend for site-specific drug delivery and targeting

List of biosensors in the literature based on nanowires.

Type of biosensor

Aim

References

Silicon nanowire field-effect transistors

Detection of proteins, DNA sequences, small molecules, cancer biomarkers, and viruses

[83]

NanoVelcro chip with nanowires

Developed for single-circulating tumor cell isolation

[78]

Silicon nanowire-based electrical cell impedance sensor

Detection of cancerous cultured living lung cells

[80]

Nanowire-based field-effect sensor devices (which can be modified with specific surface receptors)

Used as a powerful detection device for a broad range of biological and chemical species in solution

[84]

direct electrical detection of various biomolecules. A comparative analysis of biofunctionalization strategies needs to be discussed to design and develop optimum memristive biosensors to be implemented in label-free sensing applications. The surface of the device is modified with a specific antigeneantibody via: (1) direct adsorption on the device surface, (2) a bioaffinity approach using the appropriate combination, and (3) the optimum memristive biosensor, which is defined via the calibration and comparative study of biosensors’ electrical response under controlled environmental conditions, such as humidity and temperature, aiming to maximize the performance of the biosensor. This modified system shows potential for general application in molecular diagnostics, and, in particular, for the early detection of cancer, namely, prostate [82] (Table 1.4). Some investigators of the University of San Diego have been developing nanowires with the purpose of recording the electrical activity of neurons in fine detail. The ambition of the group is that one day this new nanowire technology could serve as a method to screen drugs used specifically in neurological diseases, which could help researchers to understand the mechanism of how single cells can communicate in complex neuronal networks. The main objective is to allow the scientific community to delve deeper into how the brain works. In the future, the goal of researchers is to implant this new nanowire technology into the brain [85].

4.3 Nanowires for delivery of chemotherapeutics Sharma et al. developed noncytotoxic, magnetic, Arg-Gly-Asp (RGD)-functionalized nickel nanowires (RGD nanowires) that could trigger specific cellular responses via integrin transmembrane receptors, resulting in the dispersal of nanowires [86]. Their results showed that dispersal of 3 mm long nanowires increased considerably with functionalization by RGD when compared to PEG, through integrinspecific binding, internalization, and proliferation in osteosarcoma cells. Additional results showed that a 35.5% increase in cell density was observed in the presence of RGD nanowires when compared to an increase of only 15.6% with PEG nanowires. These results are very promising to advance applications of magnetic nanoparticles in drug delivery, hyperthermia, and cell separation where uniformity and high efficiency in cell targeting are desirable. Contreras et al. showed that magnetic nanowires with weak magnetic fields and low frequencies could induce cell death via a mechanism that does not involve heat production [87]. The low-power field exerted a force on the magnetic nanowires, causing a mechanical disturbance to the cells. In their results, cell viability studies showed that the magnetic field and the nanowires had separately decreased deleterious effects on the cells. On the other hand, when combined, the magnetic field and nanowires

4. Applications of nanowires

caused cell viability values to drop by up to 39%, depending on the strength of the magnetic field and the concentration of the nanowires. Cell membrane leakage experiments showed membrane leakage of 20%, which proved that cell death mechanisms induced by nanowires and magnetic fields involve cell membrane rupture. Thus these results suggested that magnetic nanowires can kill cancer cells. The advantages of this process are the use of simple and low-cost equipment with exposure to only very weak magnetic fields for brief time periods. Another alternative is ultrasound-powered nanowire motors based on nanoporous gold segments that are developed for increasing drug loading capacity. These nanowire porous motors are characterized by a tunable pore size, high surface area, and high capacity for the drug payload. These highly porous nanomotors are prepared by template membrane deposition of a silver/gold alloy segment followed by dealloying the silver component. The chemotherapeutic drug doxorubicin was loaded within the nanopores via electrostatic interactions with an anionic polymeric coating. The nanoporous gold structure facilitates near-infrared lightcontrolled release of the drug through photothermal effects, which is a great advantage. Incorporation of the nanoporous gold segment leads to a nearly 20-fold increase in the active surface area compared to common gold nanowire motors [88]. The latter work offers very important information for the treatment of cancer patients at a patient-specific level based on specific drug responses of circulating tumor cells. So, platforms for high capture efficiency of circulating tumor cells are essential for clinical evaluation of patient-specific drug responses of circulating tumor cells. Recently, nanostructure-based platforms have been developed. In the Kim et al. study, the breast carcinoma cell-line with an ultralow abundance range was captured by streptavidin-functionalized silicon nanowire platforms for evaluation of capture efficiency

9

[89]. In this case, a capture efficiency of more than 90% was achieved. Specific drug responses of breast carcinoma cell-line cells captured on these platforms were analyzed using tamoxifen or docetaxel as a function of incubation time and dose. In addition, circulating tumor cells were successfully captured, and this study suggests that this platform is adaptable for clinical use in the evaluation of circulating tumor cells and drug response tests. Magnetic silica core/shell nanovehicles presenting atherosclerotic plaque-specific peptide-1 as a targeting ligand have been prepared through a double-emulsion method and surface modification with magnetic iron oxide (Fe3O4) nanoparticles. The results demonstrated that under a high-frequency magnetic field, magnetic carriers incorporating the anticancer drug doxorubicin collapsed, releasing approximately 80% of the drug payload, due to the heat generated by the rapidly rotating Fe3O4 nanoparticles, thereby realizing rapid and accurate controlled drug release. At the same time, the magnetic Fe3O4 could also kill the tumor cells through a hyperthermia effect, i.e., inductive heating. The combination of remote control, targeted dosing, drug-loading flexibility, and thermotherapy and chemotherapy suggests that these magnetic nanovehicles have great potential for application in cancer therapy [90]. Another study showed that an electroresponsive drug release system based on polypyrrole nanowires was developed to induce the local delivery of the anticancer drug doxorubicin, according to the applied electric field. These nanowires were initially prepared by electrochemical deposition of a mixture of pyrrole monomers and biotin as dopants in the anodic alumina oxide membrane as a sacrificial template. Additionally, the antitumor efficacy of doxorubicin released from these nanowires in response to the external electric field using two kinds of cancer cell lines, human oral squamous carcinoma cells and human breast cancer cells, was investigated. An advantage of these

10

1. Bioactive hybrid nanowires: a new in trend for site-specific drug delivery and targeting

particles is the strong photothermal effect as a result of the near-infrared absorbing ability of polypyrrole synergistically that, as a consequence, maximizes chemotherapeutic efficacy, which is very promising for many therapeutic applications, including cancer [91]. To detect specific mRNA sequences, essential in the treatment of cancer, molecular beacons have been widely employed as sensing probes. Kim et al. developed a nanowire-incorporated and pneumatic pressure-driven microdevice for rapid, high-throughput, and direct molecular beacon delivery to human breast cancer MCF-7 cells to monitor survivin mRNA expression [92]. This microdevice is composed of three layers: (1) a pump-associated glass manifold layer, (2) a monolithic polydimethylsiloxane membrane, and (3) a ZnO nanowire-patterned microchannel layer. The molecular beacons are immobilized using the ZnO nanowires by disulfide bonding, and the glass manifold and monolithic polydimethylsiloxane membrane serve as a microvalve. The cellular attachment and detachment on the molecular beacon-coated nanowire array can be easily manipulated. All these procedures enable the transfer of molecular beacons into the cells in a controllable way with high cell viability and are useful to detect survivin mRNA expression quantitatively after docetaxel treatment [92]. Combination therapy is a promising cancer treatment strategy that is usually based on the utilization of complex nanostructures with multiple components. Ultrathin tungsten oxide nanowires (W18O49) were synthesized using a solvothermal approach and were examined as a multifunctional theragnostic nanoplatform [93]. In vitro and in vivo analyses demonstrated that these nanowires could induce extensive heat- and singlet oxygen-mediated damage to cancer cells under 980 nm near-infrared laser excitation. The comparison of near infraredinduced photothermal therapy/photodynamic therapy and radiation therapy alone showed

that W18O49-based synergistic trimodal therapy eradicated xenograft tumors, and no recurrence was observed. In conclusion, these nanowires have shown significant potential for cancer therapy with inherent image guidance and synergistic effects from phototherapy and radiation therapy, which warrants further investigation [94].

5. Conclusions This chapter summarizes the critical results obtained using nanowire structures as a platform useful in bioanalytical chemistry and medical diagnostics. Nowadays, there are various technical approaches to develop nanowires for bioapplications in molecular to cellular levels. Nanowires have been integrated with microchannels, providing a novel pathway from the macroscale to the nanoscale that will allow researchers to observe and analyze target molecules such as DNA, RNA, proteins, and circulating tumor cells. Another benefit of nanowires is their very small diameter size with high aspect ratio; this can allow researchers to use nanowires as a probe tip to stimulate and record changes in electrical signals in living cells. Nanowires were also used as biological optical sensors. These improvements in nanowire structures will allow the development of new bioanalytical chemistry and medical diagnostics tools that will open a new age of nanotechnology with the widespread use of nanowires for bioapplications.

Acknowledgments The authors acknowledge the financial support received from the Portuguese Science and Technology Foundation (FCT/ MCT) and from European Funds (PRODER/COMPETE) under the project reference M-ERA-NET/0004/2015-PAIRED, cofinanced by FEDER, under the Partnership Agreement PT2020.

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C H A P T E R

2 Opportunities and challenges of 3D-printed pharmaceutical dosage forms Adam Procopio1, Divya Tewari2 1

Merck & Co., Inc., Kenilworth, NJ, United States; 2Noramco Inc., Wilmington, DE, United States

1. Introduction

product (Spritam) that uses a 3DP technology based on powder layering launched by Aprecia Pharmaceuticals. There are existing examples of implementing 3DP technology to rapidly prototype release rates using different strategies, largely focused on maintaining a similar material feedstock and using creative printing parameters to generate various releases. With these examples, at least one solid filament material is preprocessed to contain active pharmaceutical ingredients (APIs). Modifications to what is called the “infill” parameters of the printed tablet can manipulate release rates [1be3]. During a fused deposition modeling (FDM) printing process, the print head will print an outer shell in the shape of the part, and the inside of the shell is largely hollow. The material that is printed on the inside of the shell is called the infill and can be controlled through software by taking into account what percentage of the shell is hollow and the geometric design of the infill (honeycomb, rectilinear, etc.). Other published work involves the changing of the active dosage form’s overall shape, size, and surface area, which has

Drug product development can be a long and complex process. On average, it is estimated that it takes about 10 years and costs US$2.5e5 billion for a new drug product to get to the market [1,1a]. Given this significant investment, and the knowledge that any delay in getting the drug product to the market reduces exclusivity, there is a desire to reduce this development timeline providing an overall benefit to patients and the industry. 3D printing (3DP) can allow for a robust, flexible, and costeffective approach to drug development in which drug release profiles may be tailored to a particular outcome using a single manufacturing method. Moreover, 3DP allows for custom designs and dosing amounts such that the dosage forms may be tailored to a specific patient population. Due to longer and complex formulation processes, development of delayed or extended release formulations is typically even more prolonged as well as requiring expensive and propriety drug release technology. To date there is only one approved

Drug Delivery Trends https://doi.org/10.1016/B978-0-12-817870-6.00002-X

15

© 2020 Elsevier Inc. All rights reserved.

16

2. Opportunities and challenges of 3D-printed pharmaceutical dosage forms

shown to modify the release rate [4e7]. Manufacturing of drug product dosage forms that combine a shell-based approach to be described in detail in a later section have demonstrated a unique ability to generate distinct release rates. Such core/shell tablets have been manufactured by using a second API-containing material [8] or a placebo material with the intent to mimic enteric-coated tablets [9,10] and have demonstrated the agility of 3DP to change the onset of the release of the core of the dosage form. While these approaches have demonstrated an ability to use software for tuning drug release rate while maintaining a constant material feedstock, they are reliant on a successful hot melt extrusion (HME) formulation of a printable filament for each API. Developing process conditions to incorporate API into an excipient-based solid filament is not trivial [11e14], and these filament processing developments add to the product development burden, reducing the rapid prototyping advantage 3DP brings to the table for early drug screenings. A major hurdle the pharmaceutical 3DP field has yet to overcome is providing a wide, distinct range of dosage forms using a universal set of starting print-ready materials to accommodate any API without filament formulation burden, and has even a greater hurdle on aligning manufacturing partners to generate good manufacturing-processed pharmaceutical materials that are printer ready.

2. Materials Pharmaceutical dosage form design begins with material selection. Because the materials are altered during the 3DP process, it is imperative to understand the source, purity and associated material chemistry changes of

the chosen material. Material properties have wide-ranging impact, from influencing the preferred route of manufacturing to the physical properties of the dosage form to its pharmacodynamic fate in the body. A wide range of materials are used as substrates in 3DP; however, because of their origin in industrial prototyping, most 3DP techniques lack availability of suitable developed materials [15]. The successful design and printability of the 3D-printed dosage forms is dictated by the physical, chemical, thermal, and mechanical properties of the chosen material. Additional considerations should be given to ease of availability and the regulatory status of the materials. In the absence of the standard test methods a specifically designed method to characterize the material properties of the additives can be used, and we have compiled current test procedures employed by various researchers and highlighted some of the standard utilized ASTM methods. The range of polymers used in 3DP include thermoplastics, thermosets, elastomers, hydrogels, functional polymers, polymer blends, composites, and biomaterials [16]. Polymeric materialsdpolymersdconstitute the majority of materials used in 3DP due to several advantages such as low cost, biocompatibility, availability, ease of processing, and physicochemical properties. Material selection is dictated by the choice of the 3DP technology, e.g., polymeric filaments used by FDM must have a constant diameter of 1.75 mm, an ideal melt viscosity to facilitate viscous melt formation preextrusion and solidification postextrusion, and a sufficient elastic modulus-to-melt viscosity ratio to prevent filament buckling and shear thinning tendencies in liquid form [17]. Commonly used polymers include aliphatic polyesters (poly(lactide) [PLA], poly(glycolide), poly(caprolactone) [PCL]), cellulosic derivatives

17

2. Materials

(hydroxypropylcellulose [HPC], hypromellose [HPMC], HPMC acetate succinate [HPMCAS], cellulose acetate, and cellulose acetate phthalate), vinyl polymers (polyvinylpyrrolidone [PVP] and copovidone), polyethylene oxide, polyethylene glycol (PEG), and acrylic polymers (Eudragit). Table 2.1 provides an overview of 3DP technologies and desired material properties required for successful development of 3Dprinted dosage forms.

TABLE 2.1

2.1 Aliphatic polyesters Aliphatic polyesters are synthetic homopolymers or copolymers of lactic acid, glycolic acid, lactide, glycolide, and 6-hydroxycaproic acid. Typically, the molecular weights of homopolymers and copolymers range from 2000 to >100,000 Da. The representative chemical structures are provided in Fig. 2.1 and a brief summary of their physical, chemical, and mechanical properties is outlined in Tables 2.1 and 2.2.

Summary of material properties and test methods commonly employed.

Material properties

Key properties

Testing methods commonly employed

Powder physical properties

Particle shape, particle size distribution, bulk and tap densities, crystallinity, moisture content

Laser light diffraction, densitometry, powder X-ray diffraction, differential scanning calorimetry, Karl Fischer, flow index

Mechanical properties

Yield strength, elasticity, modulus, elongation at break

ASTM D638, D3039, D882, ISO 527-2, three-point bend test

Thermal properties

Melting point, glass transition temperature, degradation temperature

Thermogravimetric analysis

Optical properties

Ultraviolet absorption, laser power

Rheological properties

Viscosity of the solution, binderepowder interaction, melt viscosity, melt index, surface tension

FIGURE 2.1

AERS-G2 rheometers, viscometers (USP 911), ASTM D1238

Representative chemical structures of the aliphatic polyesters.

18 TABLE 2.2

2. Opportunities and challenges of 3D-printed pharmaceutical dosage forms

Typical chemical names and trade names of the representative aliphatic polyesters. Composition

Generic name

Lactide

Trade name

Manufacturer

Poly(L-lactide)

100

0

0

Lactel L-PLA 100L Resomer L206 S, 207S, 209 S, 210 and 201 S

Durect Lakeshore Boehringer Ingelheim

Poly(DL-lactide)

100

0

0

Lactel DL-PLA Purasorb PDL 02A, 02, 04, 05 Resomer R 202 S, 202 H, 203 S, 203 H

Durect Purac Boehringer Ingelheim

85

15

0

Resomer LG 855 S, 857 S

Lakeshore Boehringer Ingelheim

Poly-ε-caprolactone

0

0

100

Lactel PCL 100 PCL

Durect Lakeshore

Poly-(DL-lactide-coε-caprolactone)

85

0

15

8515 L/PCL

Lakeshore

Poly(L-lactide-co-glycolide)

Glycolide

Caprolactone

Adapted from Handbook of Pharmaceutical Excipients.

Aliphatic polyesters are United States Food and Drug Administration (FDA) and European Medicine Agency approved, versatile thermoplastic polymers that are used in a number of 3DP technologies such as FDM, selective laser sintering (SLS), pressure-assisted microsyringes (PAMs), etc. due to their biocompatibility, biodegradability, high mechanical strength and modulus, and processability [18]. Ease of availability and cost effectiveness make aliphatic polyesters highly desirable polymers for 3DP, whereas the main disadvantages are the appearance of rough surfaces and low resolution. PLA is by far the most widely used material for FDM printing. PLA and its derivatives are poorly water soluble but have good solubility in dioxane, acetonitrile, chloroform, methylene chloride, 1,1,2-trichloroethane, and dichloroacetic acid. The thermal and mechanical properties of PLA are influenced by small amounts of enantiomeric impurities. Amorphous grades were reported to have better processability

and a wider processability window but lower mechanical properties [19] (Table 2.2). PCL is a hydrophobic polymer with excellent blend compatibility with many other polymers such as polyvinyl(acetate), poly(vinylchloride), poly(styrene-acrylonitrile), and poly(acrylonitrile butadiene styrene). Its blend compatibility, biodegradability, low melting point, and solubility make this polymer suitable for precise extrusion deposition and FDM techniques. The only disadvantage of PCL is its hydrophobicity, which might adversely impact drug dissolution characteristics.

2.2 Cellulose ethers and esters Cellulose is the most abundant naturally occurring polysaccharide. Each polysaccharide unit is linked by b-1,4-glycosidic bonds. Each glucose unit has three hydroxyl groups that can be derivatized and the average substitution grade cannot exceed three. Alkalization of

2. Materials

cellulose, followed by etherification reaction at elevated temperatures and pressures, is used to convert cellulose molecules into their corresponding ether, such as HPC, HPMC, and many other semisynthetic cellulosics. Esterification of the cellulose ethers could be used to derive molecules such as HPMCAS. At the basic level, cellulose derivatives are characterized by their average molecular weight distribution and average composition. Compositionally, these polymers are defined by the percent weight of the functional group attached to the backbone, the degree of substitution per anhydroglucose, or the total molar substitution per anhydroglucose residue [20]. The representative chemical structures are provided in Fig. 2.2 and a summary of their physical, chemical, and mechanical properties is provided in Table 2.3.

19

Thermoplastic polymers are typically materials of choice in 3DP coupled with extrusion because they can be processed at suitable temperatures without affecting the stability of the APIs [21]. Cellulose esters and ethers have been tested as carriers or matrices for drugs in FDM technology with HME [22]. HPMC in either solution, dispersion, or paste forms has also been used in PAMs printing technology [23].

2.3 Acrylic polymers Polymethacrylates are synthetic cationic and anionic polymers of dimethylaminoethyl methacrylates, methacrylic acid, and methacrylic acid esters in varying ratios [24]. Eudragit polymers are copolymers derived from esters of acrylic and methacrylic acid whose

FIGURE 2.2 Representative chemical structures of cellulose ethers and esters.

20

2. Opportunities and challenges of 3D-printed pharmaceutical dosage forms

TABLE 2.3

Typical physical and mechanical properties of the aliphatic polyesters. L-PLAa

8515 L/PCLb

DL-PLAa

PGAa

PCLa

85/15 DL-PLGa

40,000e100,000

>100,000

80,000e150,000

40,000e100,000

173e178

Amorphous

225e230

58e63

Amorphous

Amorphous

Glass transition temperature (
C)

60e65

50e60

35e40

65 to 60

50e55

20e25b

Color

White

White

Light tan

White

White to light gold

Tensile strength (psi)

8,000e12,000

4,000e6,000

10,000þ

3,000e5,000

6,000e8,000

3,254

Elongation (%)

5e10

3e10

15e20

300e500

3e10

>6.4

Modulus (psi)

4e6  10

Properties

Molecular weight (Da) 40,000e100,000 Melting point

(
C)

5

2e4  10

5

1  10

6

3e5  10

4

2e4  10

5

8.4  104

PCL, Polycaprolactone; PGA, poly(glycolide); PLA, poly(lactide); PLG, poly(lactide-co-glycerol). a Specifications from Durect, b Specifications from Lakeshore Biomaterials and process temperature range 140e160
C. Adapted from Handbook of Pharmaceutical Excipients.

physicochemical properties are determined by functional groups. Several compositional copolymer variants are derived from esters of acrylic and methacrylic acid, whose physical, chemical, mechanical, and thermal properties are determined by the functional groups. The representative chemical structures and summary of typical trade names and suppliers is provided in Fig. 2.3 and Tables 2.4e2.6, respectively. Acrylic polymers have been used for FDM [11,12], binder jetting additive manufacturing, and SLS printing technologies [25e28].

2.4 Vinyl polymers Polyvinyl alcohol (PVA) polymers and PVP polymers and copolymers are important

FIGURE 2.3 Representative chemical structures of acrylic polymers.

members of this product family. PVA is a water-soluble synthetic polymer represented by the formula (C2H4O)n. It is a synthetic, linear, semicrystalline polymer produced via the hydrolysis of polyvinyl acetate in methanol, ethanol, or a mixture of alcohol and methyl acetate, using alkalis or mineral acids as catalysts. Unlike other vinyl polymers, it is not produced via the polymerization of repeating units of vinyl alcohol because it cannot be obtained in the quantities and purities required for polymerization purposes. It is manufactured by hydrolysis of polyvinyl acetate and the removal of acetate groups. It has low solubility in ethanol and is insoluble in many organic solvents. Its physical properties are dictated by the degree of polymerization and the degree of hydrolysis. The pharmaceutical grades are partially hydrolyzed and available in different viscosity types. PVPs or povidone are water-soluble linear synthetic polymers, manufactured by free radical polymerization of N-vinylpyrrolidone. Vinylpyrrolidone-vinylacetate copolymer or copovidone (PVP/VA) are water-soluble copolymers of the two components in the ratio of 6:4. It is also produced by free radical polymerization

21

2. Materials

TABLE 2.4

Typical chemical names and trade names of the representative cellulosic polymers.

Generic name

Assay

Trade name (grades)

Manufacturer

Hydroxypropylcellulose

% Hydroxypropoxy 53.4e80.5a

Klucel HPC (Klucel EL, LF, GF) Nisso HPC (Nisso-L)

Ashland Nippon Soda Nisso (Seppic)

Hydroxypropylmethylcellulose

Type 2910 % Hydroxypropoxy 7.0e12.0 % Methoxyl 28.0e30.0 Type 2208 % Hydroxypropoxy 4.0e12.0 % Methoxyl- 19.0e24.0

Methocel HPMC (Methocel E3, E6, E10, K100LV, K4M) Klucel HPMC (Benecel K100LV PH PRM, Benecel K4M)

DuPont Specialty Solutions (previously Dow Wolff Cellulosics) Ashland ShinEtsu Lotte Fine Chemical

Hydroxypropylmethylcellulose acetate succinate

% Hydroxypropoxy 4.0e23.0 % Methoxyl 12.0e28.0 % Acetate-2.0 16.0 % Succinate 4.0e28.0

Aqoat HPMCAS (LG, MG, HG) Affinisol HPMCAS (LG, MG, HG) Aquasolve HPMCAS (LG, MG, HG)

ShinEtsu DuPont Specialty Solutions Ashland

Ethylcellulose

% Ethoxyl 44.0e51.0

Aqualon ethylcellulose (N types) Ethocel ethylcellulose (N types)

DuPont Specialty Solutions (previously Dow Wolff Cellulosics) Ashland

a

Specifications from USP 41-NF 36.

reaction in an organic solvent such as ethanol or 2-propanol [29]. The representative chemical structures, commercial supplier information, and polymer properties are given in Fig. 2.4 and Tables 2.7 and 2.8, respectively. PVA is a thermoplastic, water-soluble excipient that is commonly employed as polymeric support material for FDM-based 3DP [5,6,8,30,43,44]. The degree of hydrolysis impacts the physicochemical, thermal, and mechanical properties of the resultant PVA grade. Besides FDM printing, PVA has also been used in inkjet printing [31]. PVP and PVP/VA polymers are known for their application in the solubility enhancement of poorly water-soluble drugs via HME. Due to the complementarity of HME technology with

FDM, polymers used in HME are frequently adapted for use in 3DP. Additives, such as plasticizers and fillers, are usually employed to reduce the Tg of PVP polymers and render them suitable for FDM printing coupled with HME. Major et al. examined the material properties of PVP/VA copovidone copolymers in hot melt extrusion-based 3DP and encountered difficulties in printing due to brittleness and high stiffness of the copolymer. Melt blending with a carrier polymer such as PCL improved flexibility and ductility thereby resolving the printability issue. Polyethylene oxide was also added to the formulation to reduce the negative impact of PCL on drug release profiles [32]. Melt blending PVP/VA with hydrophilic polymers such as HPMC and HPMCAS resulted in immediate release formulations [33].

22 TABLE 2.5

2. Opportunities and challenges of 3D-printed pharmaceutical dosage forms

Typical physical, mechanical, and thermal properties of the cellulose polymers.

Properties

Klucel HPCa

Benecel HPMC

AquaSolve HPMCAS

Aqualon ethylcellulose

Molecular weight (Da)

40,000e1,150,000

20,000e1,200,000

55,000e93,000d

75,000e215,000f

Melting point (
C)

Softens at 130

190e200

Glass transition temperature (
C)

0 and 120b

170e180

120e125

129e133e

Color

White to slightly yellow colored

White to off-white powder

White to off-white powder or granuled

White to light tan-colored powdere

Tensile strength (psi) (ASTM D882)

1450 (Klucel HPC EF)

6816 (Benecel HPMC E6)

5076 (HPMCAS L) 5366 (HPMCAS M) 5802 (HPMCAS H)g

6899

Elongation (%) (ASTM D882)

12 (Klucel HPC EF)

4 (Benecel HPMC E6)

11 (HPMCAS L) 19 (HPMCAS M) 16 (HPMCAS H)g

9

Modulus (psi) (ASTM D882)

200,000e630,000c (grade dependent)

367,090 (Benecel HPMC E6) 1574 (L) 1523 (M) 1494 (H)g,h

156f

302,403

a

Adapted from Klucel HPC Physical and Chemical Properties Book (https://www.ashland.com/file_source/Ashland/Product/Documents/Pharmaceutical/ PC_11229_Klucel_HPC.pdf), b Klucel HPC is a special polymer that can show dual Tg because it has a beta transition, c Reference [21], d Handbook of Pharmaceutical Excipients, Sixth Edition, 330e332, e Handbook of Pharmaceutical Excipients, Sixth Edition, 262e267, f Aqualon Ethylcellulose EC Physical and Chemical Properties, Product Brochure-PRO 250-42a, g PC-12624 AquaSolve HPMCAS Handbook, h Handbook of Pharmaceutical Excipients, Sixth Edition, 326e329.

2.4.1 Novel polymers in the market Melfil is a water-soluble filament of butanediol vinyl alcohol copolymer specifically designed for FDM 3DP. It offers superior water solubility and printability along with the flexibility to use as a support material or a watersoluble model (see the Nippon GohseidMelfil Product Brochure [53]). Thermoplastic polyurethanes (TPUs) are elastic and melt processable linear-segmented block copolymers. TPUs offer a unique advantage over other thermoplastic polymers because of their extreme material adaptability. This is due to the flexibility in modifying the molecular weight, ratio, and chemical composition of soft

(polyether or polyester based) and hard segments (aliphatic or aromatic based) of the TPUs [34]. Polyether ether ketone (PEEK) and polyether imide (PEI, brand name ULTEM) are newer thermoplastic semicrystalline materials from the polyaryletherketone (PAEK) family of polymers currently used in FDM printers [35]. PAEK polymers can withstand high temperatures while maintaining mechanical strength [36]. PEEK is a superhigh-performance, biocompatible, chemically stable, semicrystalline plastic that offers the advantages of high-temperature resistance (melting point of 334
C, Tg of 143
C) and excellent mechanical properties, including high

23

2. Materials

TABLE 2.6

Typical chemical names and trade names of the representative acrylic polymers.

Generic name

Polymer dry weight content (%) Trade name (supply form)

Poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) 1:2:1

98% 12.5% 98%

Eudragit E 100 (granules) Eudragit E 12.5 (organic solution) Eudragit E PO (powder)

Evonik Industries

Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2

97% 97% 30%

Eudragit RL 100 (granules) Eudragit RL PO (powder) Eudragit RL 30 D (aqueous dispersion)

Evonik Industries

Poly(methacrylic acid, ethyl acrylate) 1:1

95% 30% 95% 30% 30% 95%

Acryl-EZE (powder) Eudragit L 30 D-55 (aqueous dispersion) Eudragit L 100-55 (powder) Eastacryl 30 D (aqueous dispersion) Kollicoat MAE 30 DP (aqueous dispersion) Kollicoat MAE 100 P (powder)

Colorcon Evonik Industries Eastman Chemical BASF Fine Chemicals

Manufacturer

Adapted from Handbook of Pharmaceutical Excipients.

FIGURE 2.4 TABLE 2.7

Representative chemical structures of vinyl polymers.

Typical chemical names and trade names of the representative vinyl polymers.

Generic name

Polymer dry weight content (%)

Trade name (grades)

Manufacturer

Polyvinyl alcohol (PVOH/PVA)

Degree of hydrolysis 86.5e89.0

Goshenol EG Granules/Powder (EG-03P, EG-05P, EG-18P, EG-22P, EG-30P, EG-40P)

Nippon Synthetic Chemical Company

Polyvinylpyrrolidones (PVP, Povidone)

K value- 25-90

Kollidon povidone Plasdone povidone

BASF Ashland

Polyvinylpyrrolidone: vinylacetate 6:4 (PVP/VA, Copovidone)

K value - 25.4-34.2a,b

Kollidon VA 64 copovidone Plasdone S630 copovidone

BASF Ashland

a

http://www.nichigo.co.jp/english/lifechemical/pharma/index.html, b From the Ashland brochure. Adapted from Handbook of Pharmaceutical Excipients.

24

2. Opportunities and challenges of 3D-printed pharmaceutical dosage forms

TABLE 2.8

Typical physical, mechanical, and thermal properties of the vinyl polymers. Copovidonea

Properties

PVA

Povidone

Molecular weight (Da)

20,000e200,000b

28,000e1,150,000

(
C)

45,000e75,000

150
Cc

180e190 for partially hydrolyzed grades 228 for fully hydrolyzed grades

Softens at

Glass transition temperature (
C)

85

120e175d

106

Color

White to cream-colored granular powder

White to creamy white powderc

White to off-white free-flowing powder

Tensile strength (psi)

44,961e

Films brittle; difficult to assess pure film properties

Melting point

e

Elongation (%)

2

Modulus (psi)

20,305e

140

PVA, Polyvinyl alcohol. a Specifications from the Ashland brochure, b Handbook of Pharmaceutical Excipients, Sixth Edition, 564e565, c Handbook of Pharmaceutical Excipients, Sixth Edition, 581e585, d Ashland Literature PTR-092 Plasticizer compatibility and thermal and theological properties of Plasdone povidone and copovidone polymers for hot-melt extrusion applications, e Hamied, S.F.A; Abd El-Kader, K.A.M. Preparation of poly (vinyl alcohol) films with promising physical properties in comparison with commercial polyethylene film.

strength, elastic modulus, and fracture toughness [37]. PEI was developed by General Electric’s plastics division in the 1980s (later acquired by SABIC) and demonstrates superior thermal properties and mechanical strength characteristics of the family. 2.4.2 Additives Plasticizers, fillers, and lubricants are common additives used to improve printability by either modifying the melt and mechanical properties [33] or reducing the friction between the filament and walls of the printing extruder [10]. Commonly used additives include fillers such as talc, lactose, microcrystalline cellulose, magnesium stearate, and tricalcium phosphate, or plasticizers, such as triethyl citrate, triacetin, PEG 400, Tween 80, etc.

3. Technology details 3DP has been gathering significant attention from both industry and academicians. Research efforts have spanned the applications of both novel drug delivery to replacement/supplement of traditional manufacturing approaches. To accommodate these various manufacturing modes, different 3DP approaches are employed. This section reviews the available technologies along with their advantages and disadvantages from a technical point of view. In general, the technology is built on the principle that matter is converted from either liquid to solid or undergoes a transition from solid to liquid back to solid in a layer-by-layer approach either through chemical means or thermal energy. The contributing limitations to either print resolution or print speed are a result of the fundamental

25

3. Technology details

mode of the physics used in the print process. ASTM ascribes seven different 3DP technologies (ASTM F2792). We discuss here the top three technologies that are most relevant for the pharmaceutical industry: 1. Vat photopolymerization 2. Powder-based processes 3. Material extrusion The aim here is not to describe all of these technologies in detail but to cover the 3DP modes that have contemporaneous or direct immediate impact on the biopharmaceutical industry in their application of drug product prototyping and at-scale manufacture.

controlled both in terms of energy supplied and in the amount of time that drives the photopolymerization reaction to cross-link the liquid formulation and convert it to solid polymer precisely at the regions where the light source is focused. Vat photopolymerization has the highest lateral and vertical print resolution in the range of 1e10 mm. Lateral resolution is defined by the positional control of the light source, whereas vertical resolution is controlled by the penetration depth of the light source and any light-absorbing additives that are added to photochemical resin to control any unwanted light-scattering events. 3.1.1 Stereolithography apparatus

3.1 Vat photopolymerization Vat photopolymerization carries alternative names with concurrent differing underlying technologies such as stereolithography apparatus (SLA), digital light processing (DLP), and continuous liquid interface production (CLIP). The fundamental principle of operation is that a liquid photopolymer resin formulation comprising a monomer, oligomer, and photoinitiator is cured through selective exposure to light using a specified light source (most typically a 450 nm laser) either in a raster mode or as a projected 2D image (e.g., DLP). The light source is

Fig. 2.5 depicts the principal components of a typical SLA printer. The platform is precisely controlled in concert with the position of the focused laser source and any mirrors used to direct the light source to sequentially scan or project the laser light source within a plane on the surface of the photosensitive resin formulation. The time spent on any individual 2D layer depends on the chemistry of the resin formulation to successfully complete the cross-linking reaction and convert the liquid formulation to solid polymer resin. The lateral (xey) position of the laser is typically controlled with a pair of mirrors within servo-controlled galvanometers, Laser

Vat

FIGURE 2.5

SLA Photo resin

3D Printed Object

Y plaorm

Principal components of a stereolithography apparatus (SLA) printer.

26

2. Opportunities and challenges of 3D-printed pharmaceutical dosage forms

which are electromechanical instruments used to precisely control the position of the mirror and hence the position of the laser spot location. This process is conducted layer by layer whereby the slicing software converts the 3D image to be printed into a series of control statements that ascribe not only the position of the platform position, but also the laser energy pulse and well as the tilt angle of the mirrors used to position the xey position of the spot. A unique feature of photopolymerization 3D printers is the ability to resolve fine details by the application of galvanometer dithering (or high-frequency movements) to effectively process grayscale images that prescribe laser energy states between full on or full off. This technique allows for the creation of highly resolved surfaces. In general, photopolymerization techniques allow for highly resolved features and surfaces on the order of 1 mm. Their main disadvantages are extremely limited for use as a biopharmaceutically acceptable process in that they are using both toxic monomer and oligomer materials and usually have lengthy postprocessing steps to remove any unreacted monomer and oligomer as well as completely consume any unreacted free radicals as a result of photochemistry. The materials available for creating 3DP drug products from photochemical reactions are limited but research in this area is evolving. 3.1.2 Digital light processing DLP is analogous to SLA because both processes use a controlled wavelength light source to selectively drive a photochemical reaction of a resin formulation. The main difference between SLA and DLP is that the light source in SLA acts as an XeY rastering, whereas in DLP the entire layer to be cured is projected onto the focal plane at one time. The technology used with DLP is the same technology used in overhead projectors, which allows for dithering as described in the SLA section earlier and for grayscale image processing and hence higher resolution features and smoother printed

surfaces. Unlike SLA where the photochemical reaction is near the liquid/air interface and subject to oxygen inhibition less direct control of the photochemical cross-linking reaction, DLP 3D printers are controlled in the reverse direction where the reaction layer occurs at a plane immersed well below the liquid/air interface. An example of the application of DLP in 3DP is the work by Kim et al. with precision bioprinting of silk fibroin bioink for applications in building complex organ structures [38]. 3.1.3 Continuous liquid interface production The latest variety of vat photopolymerization is CLIP [39,40]. This technology addresses the major time-limiting step of both SLA and DLP, which is the required mechanical separation of the just-cured material from the vat of unpolymerized material. This 3DP technique uses an oxygen permeable membrane to inhibit polymerization at the interface nearest to the ultraviolet (UV) light source. This region creates a 10e100 mm “dead zone” where free radical polymerization does not occur. Just above this zone, light-catalyzed free radical polymerization occurs on the focal plane of the projected light. This innovation is key to facilitate a faster 3DP process because the need to refresh or recoat the region between the printed part and the light source using a mechanically activated platform is not needed. Using CLIP, this region is continuously present with uncured formulation and the 3D-printed part appears to “grow” out of the resin. Resolution of the part in the vertical direction is improved by increasing the concentration of the passive light absorber. This slows down the production speed because light penetration is in a smaller volume of the resin. By lowering the concentration of this additive, deeper penetration of light can be realized and hence faster production speeds. Part quality is also improved by removing the need to mechanically separate the part from the resin bath. This mechanical separation that is typical in most SLA 3D

3. Technology details

printers causes undue stress on the part and can lead to feature distortion or even failure. CLIP allows for both high print quality and speeds and can produce parts with features below 100 mm at growth rates in the range of a vertical support plate speed of 1000e3000 mm/h.

3.2 Powder bed fusion processes 3.2.1 Selective laser sintering process/laser sintering process Generally, laser sintering 3DP allows for many more materials over other 3DP techniques from high-performance thermoplastic polymers to even metal powders. The operating principle behind powder-based SLS consists of powder deposition from the feed chamber to the build chamber by powder transfer and consists of build surface preparation by rolling and leveling with a scraper, laser rastering and particle melting and sintering, cooling and solidification, followed by the build chamber being lowered by one-layer thickness to repeat with a recoating of fresh material from the feed chamber. During the printing process, the laser, in most applications a 2 W blue diode laser (445 nm) light source, is rastered (w100 mm/s) to match the geometry of the layer [27]. The light energy from the laser source is absorbed by the particles at the site of the laser focal spot, which in turn heats the material beyond the thermal transition (Tg or Tm) allowing for interparticle contact diffusion and binding. After removal of the light source the energy dissipates, and the newly formed coherent body solidifies. The unprinted material surrounding the printed material serves as an intrinsic support material. The fact that the 3Dprinted parts are constantly surrounded by unprinted support material means that parts can be effectively stacked and printed together to make efficient use of the build volume but it

27

also implies that a lengthy and “dirty” postprocessing is required to remove the bulk powder from the build chamber as well as the powder that is loosely adhered to the final printed part. Because of the impact of the heat-affected zone powder, not all of this unprinted powder can be reused, and it is good practice to blend virgin powder with this recycled material. One key to this technique is for the process to proceed so that enough thermal mass is present, such that not only are the particles bonded within the as-printed 2D layer, but this layer also softens/melts and binds through the same diffusional process to the layer(s) just below to form our 3D-printed part. For thermoplastic materials, liquid-phase sintering drives capillary interactions between neighboring particles resulting in bonds due to the diffusion of polymer chains or chemical cross-linking. One method that ensures a well-formed 3Dprinted part is to keep the entire 3DP chamber at a temperature just below the softening or melting point of the material to decrease the processing time and reduce thermal gradients within the part, which can lead to part distortions caused by the relatively large volume changes in semicrystalline or amorphous polymers. In this method, maintaining an elevated environment is a key consideration in the processing of thermally sensitive materials (e.g., oxidation) and would need careful evaluation depending on the material that is used for printing. To provide the best part quality and minimal part warpage, the build volume is left to cool gradually over 24e48 h for both safety in handling and to avoid distortion caused by premature handling while the parts are in a softened condition. One of the more critical criteria for this process to be effective is the flow and particle packing properties of the starting material. Because the powder deposition process between adjacent layers is done by depositing material

28

2. Opportunities and challenges of 3D-printed pharmaceutical dosage forms

through a blade and roller recoating process, the distribution of the particles across the 2D plane to be printed directly impacts part quality. If the particles do not flow and fill in the region in a uniform manner there will be voids in the final printed part. The size and sphericity of the particle properties also directly influence the surface roughness and spatial print resolution of the manufactured parts. Part resolution on the order of 100 mm is typical for a printed part. Compressibility, or volume reduction, under the roller assembly can aid in powder bed uniformity and this predensification can enable the printing of higher-density final parts. Many SLS 3D-printed parts undergo a series of postprocess finishing operations to provide more elegant surface properties. In addition, intrinsic to the type of 3DP, because of the use of powder as the starting material, final parts will be porous in nature, which may be considered as defects from a mechanical strength point of view or could aid in the disintegration of oral dosage forms as in traditional compressed tablets. For biomedical applications the porosity present in these 3D-printed parts could also serve as a scaffold for cell growth. Regardless of the material used, the parts obtained by the powder bed fusion processes will typically exhibit a certain level of porosity. The amount of free volume is dependent on particle size distribution, material choice, and process parameters. The pores remaining within a green part after the additive manufacturing process represent potential weak points in models subjected to mechanical load. If high mechanical strength is required for a given application, it is therefore common practice to improve mechanical properties by means of isostatic pressing, infiltration with suitable resins, or sintering. On the positive side, SLSfabricated parts are light and porosity can be advantageous in other applications that require large surface areas, for example, scaffolds for

cell growth in tissue engineering. SLS is applicable to materials with vastly different bulk properties. Moreover, SLS powders for the same bulk material can also vary in their morphology, sintering, and melting behavior. 3.2.2 Powder binding technology Like the SLS processes, in the first step of powder binding 3DP a powder layer is deposited using a roller/scraper assembly from a feeder chamber to the build chamber. Unlike SLS, which used a thermal method of binding powder, in liquid-phase powder binding 3DP, the powder is bound together with the use of a liquid that is dispensed using an inkjet printing head. The inkjet head will either contain a solvent (e.g., water) or a solventebinder solution. In the former, the binder is contained within the powder formulation whereas if the inject print head has a solventebinder solution the binder is dispensed from the print head. The finished 3D-printed part is then cleaned of any residual powder using a combination of a vibratory plate and airflow. Much like SLS, the particle properties drive product quality and final part resolution, but unlike SLS the inkjet print head spatial resolution is lower than that of a laser spot size. This technology offers the ability to print several materials because of two reasons: either the powder loaded into the feed chamber is a blend of multiple materials or the inkjet print head could also contain a different material such as an active ingredient or a colorant. This technology is likely the closest analogy to a traditional wet granulation process because of the similarities in materials that are used. In fact, the powder binding technology is the same core process that is used by Aprecia Pharmaceuticals to manufacture the Spritam tablet. The porous nature of the powder bed process creates a dosage form that instantaneously dissolves because of the formulation and the intrinsic capillary wicking action of the dosage form.

29

3. Technology details

3.3 3D material extrusiondfused filament fabrication 3DP extrusion-based processes have seen a bolster of activity in recent years and cover a wider range of materials, including thermoplastic polymers, pastes, and thermo or UV curable gels. In this process a nozzle or piston (e.g., syringe) is fixed to a gantry that moves in xey space. After a single layer is deposited the

extrusion head or build platform moves in z space to complete the next layer. The most common extrusion-based 3DP is known as fused filament fabrication (FFF), also known as FDM. The operating principle is shown in Figs. 2.6e2.8, where the thermoplastic polymer filament with a round cross-section of 1.75 or 3.00 mm in diameter is mechanically fed using a gear-based extruder to a cartridge-heated

Connuous elevaon Build Support Plate

Photo Resin

Dead zone

3D Printed Object

Imaging Unit O2 permeable window Mirror

FIGURE 2.6

Schematic of continuous liquid interface production. Laser

Mirror

Roller and scraper 3D printed object

Thermoplasc powder

Build plaorm

Build Chamber

FIGURE 2.7

Feeder Chamber

Schematic of selective laser sintering process.

30

2. Opportunities and challenges of 3D-printed pharmaceutical dosage forms

Material Spool

Filament

Extruder Gears

Heater Element

3D printed object Nozzle Molten Bead Build plaorm

FIGURE 2.8 Operating principle of extrusion-based 3D printing process.

nozzle assembly. Process temperature is defined by the thermal properties of the polymer filament, which for amorphous polymers is above the glass transition temperature and for semicrystalline polymers is above the melting point. The melted filament forms a molten bead upon exit from the small nozzle orifice (0.1e1 mm diameter) and begins solidification at the location from which it was extruded. The resolution of an FFF-printed part is often defined by the diameter of the nozzle. Generally, a smaller nozzle results in a surface that more closely follows the profile of the 3D geometry; however, this results in an increase in print time because of the requirements of more nozzle traces to completely define the geometry as well as often slowing the print speed because of the increase in nozzle melt pressure as a result of the smaller diameter. The rheology of viscous thermoplastic polymer

is often the limiting factor for this 3DP technique. Processing not only needs to consider the speed for appropriate bead deposition but also the temperature and time required for fusion of the deposited beads onto the adjacent layers that were previously printed. Often in 3DP for a new polymer the impact of several parameters is often experimentally derived such as filament extrusion feed rate, temperature and thermal gradients, nozzle design, die swelling, polymer melt rheology, quench rate using convective air cooling, nozzle path direction, and part orientation. These parameters are optimized to improve 3DP efficiency, surface roughness, dimensional accuracy, mechanical properties, and isotropy. Many common thermoplastic materials (e.g., PLA, acrylonitrile-butadiene-styrene copolymers, polycarbonate, and polyamides), have been optimized for fused filament fabrication

4. Regulatory and quality considerations

3DP, while other more nascent thermoplastic polymers relevant for the pharmaceutical industry are still being experimented. 3.3.1 Postprocessing Across most all 3DP technologies, the final part requires additional processing steps after completion of 3DP. Depending on the printing process these steps involve either mechanical removal of material used to improve adhesion to the printing plates, removal of support material used in the printing process, chemical and/or thermal treatment of unreacted surface material, removal of unbound surface powder, or heat treatment to reduce unwanted part residual stresses. Careful consideration and execution of the postprocessing steps is crucial to ensure that the part does not suffer undue damage.

4. Regulatory and quality considerations The FDA recently issued a guidance for industry entitled “Technical Considerations for Additive Manufactured Medical Devices.” Even though medical device and combination products are regulated by the Center for Devices and Radiological Health, many elements discussed in this document highlight key considerations for additive manufactured drug products that are regulated by the Center for Drug Evaluation and Research. This guidance like most offers supplementary regulatory guidance that covers 3DP-specific recommendations. The device-specific 3DP guidance document covers (1) design for 3DP, (2) patient-matched device design, (3) software workflows, (4) controls over materials used for 3DP, (5) postprocessing considerations, (6) process validation and product acceptance testing, (7) quality, and (8) device testing considerations. It is not the intention of this section to recount this guidance document but to direct

31

the reader to key recommendations that are common for drug products. Generally, regulated products must fulfill standard Quality System requirements. Specific to 3DP of drug products, manufacturers must validate their process and establish and maintain procedures for monitoring and controlling processing parameters to ensure that the specifications of the drug product can be met with a high degree of confidence and the product performs as intended. There are numerous 3DP technologies described that can be used to manufacture drug products and hence there are different processing steps that are implemented to manufacture a quality drug product. Because of the relative novelty of 3DP, a higher level of scrutiny should be expected due to the integration of a novel manufacturing technique with traditional or novel materials that have been reprocessed or adapted to be enabled by 3DP. One unique regulatory consideration that is atypical from traditional pharmaceutical manufacturing is the utilization of software in both the design of the final product and in the control of the process to manufacture the final drug product. 3DP involves a multistep software process that is used to design and convert 3D dosage form shapes ranging from simple/traditional to complex (more on these designs will be highlighted in the sections that follow), into sliced 2D layers (using “slicer” software). This geometrical 2D information is then used as input into control software that then translates this information into print commands. To enable consistency across the industry, the FDA guidance proposes the utilization of a specific file format for additive manufacturing (ISO/ASTM 52915 “Standard specification for additive manufacturing file format”). The intention of this standard is to create a well-controlled and integrated file that describes the printed volume, material information, and the print controls and print location within the print volume. As will be highlighted later, and perhaps more unlike

32

2. Opportunities and challenges of 3D-printed pharmaceutical dosage forms

other traditional pharmaceutical applications, software processes are as critical as and, in some instances, more critical of final product quality compared to traditional pharmaceutical process hardware/critical process parameters. Quality that is governed by software is not only process control over material being handled by the printer in terms of temperature and time as was pointed out earlier, but just as important is the structure and path for the printing tool that drives the printing of the drug product. Just like other pharmaceutical processes, 3DP often uses environmentally sensitive material as a matrix and therefore needs to be handled and evaluated similarly. In addition, many physical and chemical attributes that govern product quality in traditional processes are just as important in 3DP. For example, particle size for SLS is a critical material attribute that defines not only final dosage form elegance but also mechanical strength and dissolution variability due to defect populations because of broad particle size distribution and insufficient sintering at specified locations because of voids.

TABLE 2.9

Examples of fused filament fabrication process critical process variables and failure modes.

Process variables

Failure modes

Hardware/software input/output Extrusion rate Retraction settings Nozzle temperature Nozzle size Nozzleeplatform gap Platform surface type Platform surface roughness Platform temperature Flow rate Print Speed

Voids between layers Incomplete layer print Interlayer adhesion Plateepill adhesion Stringing Temperature excursions Thermal degradation

Table 2.9 highlights some of the critical 3DP processing variables and failure modes that need to be considered when establishing the quality system for a drug product.

5. Pharmaceutical applications for drug delivery The current advantages of using 3DP for pharmaceutical dosage forms are targeted at dosage form design and patient customization. Here we detail several published accounts of applying 3DP in the production of more traditional oral dosage forms, customized oral dosage forms that highlight the ability to tailor doses and release rates to meet patient needs, as well as nonoral dosage forms that aim to provide more patient complaint dosage forms through longer acting drug delivery. Another advantage of 3DP in drug product development is the ability to circumvent the long and complex clinical R&D process. This is especially true when the work requires: increasing drug solubility by converting the active ingredient from crystalline to amorphous using processes such as spray drying or HME, protecting the active ingredient from a specific region of the gut, or altering the drug release profile to overcome pharmacokinetic-related adverse events. 3DP can allow for production of dosage forms that overcome these common R&D challenges in a cost-effective and rapid approach in a single-step process.

5.1 Tunable release technologies Currently, there are limited pharmaceutically acceptable materials available in filament form, which is the raw material feedstock for FDM printers. Many traditional polymer excipients do not have the appropriate thermal and

5. Pharmaceutical applications for drug delivery

mechanical properties for filament processing or the physical properties are altered when drug is incorporated in the filaments. To have a robust filament the polymer must be sufficiently rigid to maintain its form as it is pushed from the compression gear through the hot end nozzle orifice of the printer. The polymer should be sufficiently tough so the extruder gear of the FDM printer can gently depress and grip the filament to generate an extrusion force greater than the resistance from the molten polymer flow out of the nozzle. In addition, the melting temperature or glass transition temperature must be significantly higher than the temperature inside the printing enclosure to allow forced air cooling to rapidly quench the extrudate. The melting temperature should also be below 250
C, which is the maximum temperature allowed in most commercially available FDM printers. Finally, to maintain proper molten flow, the thermoplastic material must not degrade while it is held at elevated temperatures during the printing process for extended periods of time, usually on the order of minutes. Once a filament is extruded, X-ray computed tomography can be used as a quality check for surface or volumetric defects [40a,40b]. Diameter variations in the filament tend to strongly correlate with the quality of the final print as most commercial printers do not dynamically change the extrusion rate based on the filament’s instantaneous diameter. Typically, pharmaceutically acceptable polymers have been experimented with varying success. HPC has been used to print drug-free capsules that are manually filled and assembled postprinting [41]. Additional work has highlighted the difficulties and limitations of using FDM for printing PVA capsules where the dosage forms were printed for hand filling with placebo liquids, followed by manual assembly and sealing, and external and internal

33

surface roughness of the printed capsule walls were investigated. Typically, however, the filament that is loaded into the FDM 3D printer is preprocessed using extrusion to incorporate active ingredients, which are then used to print the final dosage form. PVP [10,41a,41b] mixed with drug in an HME process has been used with FDM to construct oral dosage forms. PVA has been most commonly used due to its beneficial mechanical and thermal properties aiding the FDM process [6,8,30,40b,42e44]. Recent work on manufacturing filaments for 3DP examined the use of Eudragit EPO, a cationic acrylic polymer with dimethylaminecontaining side chains, which is a polymer typically unsuitable for FDM due to its brittle properties [14]. This study showed that Eudragit EPO could be compounded with a plasticizer, triethyl citrate, and a nonmelting filler, tricalcium phosphate, to optimize the hardness and flexibility properties to enable printing of the filament. The same research group demonstrated the feasibility of printing an enteric-coated 3D-printed caplet using the same plasticizer and filler approach with PVP and drug-free Eudragit EPO [10]. Other extruded materials, where quinine was mixed individually with Eudragit RS, PCL, PLA, and ethyl cellulose at a 5 wt% drug loading, demonstrated viability for use as FDM filaments for preparing 3D-printed implants [44a]. It has also been demonstrated that soaking filaments in a poor or nonsolvent solution containing drug can result in diffusion of drug into the filament, although drug loading is intrinsically lower than extrusion methods [42]. To date, there are limited successful piloting examples of pharmaceutically acceptable filaments, and the surface quality of these printed dosage forms indicates more optimization is required before widespread adoption can be realized.

34

2. Opportunities and challenges of 3D-printed pharmaceutical dosage forms

As of 2019, there are numerous examples of applying 3DP to produce dosage forms in a rapid prototyping method with variable and tunable release rates within the same manufacturing step. Several examples rely on incorporating an API into the filament used in extrusion-based 3DP using a typical HME process [1,2,5,9,10,41,43,45e48] or solvent-based diffusional processes [26,42]. The primary limitation with these approaches is the limited amount of drug that can be incorporated into the filament and hence the final 3D-printed dosage form with typical drug loadings in the 1e30 wt% range. The release rates of dosage forms made by this approach are governed by either diffusion or erosion for which the volume and geometry of

the final dosage form play are key role. An advantage of this approach of manufacturing dosage forms directly from drug-loaded filament is that the final dosage forms are generally robust enough to be used immediately after printing. Figs. 2.9 and 2.10 highlights a well-known study by Ref. [5,8,43,44] where the dosage form surface area, surface area/volume, or mass were discretely controlled and thereby directly impacted the dissolution rate without changes to the formulation. Another degree of freedom in 3DP is the modification of the infill parameters of the printed tablet, which can manipulate diffusional length scales as well as the dosage form buoyancy and hence the release rates [1e3].

FIGURE 2.9 3D-printed dosage forms of various geometries using poly(lactide) as the primary matrix for tunable release rates at constant (A) surface area, (B) surface area/volume ratio, and (C) mass (scale bar in cm). Adapted from Goyanes A, Chang H, Sedoug HD, Hatton GB, Wang J, Buanz A, Gaisford S, Basit AW. Fabrication of controlled-release budesonide tablets via desktop (FDM) 3D printing. Int J Pharm 2015b;496:414e420; Goyanes A, Martinez PR, Buanz A, Basit AW, Gaisford S. Effect of geometry on drug release from 3D printed tablets. Int J Pharm 2015c;494:657e663; Goyanes A, Buanz AB, Hatton GB, Gaisford S, Basit AW. 3D printing of modified-release aminosalicylate (4-ASA and 5-ASA) tablets. Eur J Pharm Biopharm 2015a;89:157e162; Goyanes A, Wang J, Buanz A, Martínez-Pacheco R, Telford R, Gaisford S, Basit AW. 3D printing of medicines: engineering novel oral devices with unique design and drug release characteristics. Mol Pharm 2015d;12:4077e4084.

5. Pharmaceutical applications for drug delivery

35

FIGURE 2.10 Paracetamol dissolution profiles from 3DP solid dosage with surface area/volume ratio 1 in phosphate buffer (pH 6.8). Adapted from Goyanes A, Chang H, Sedoug HD, Hatton GB, Wang J, Buanz A, Gaisford S, Basit AW. Fabrication of controlled-release budesonide tablets via desktop (FDM) 3D printing. Int J Pharm 2015b;496:414e420; Goyanes A, Martinez PR, Buanz A, Basit AW, Gaisford S. Effect of geometry on drug release from 3D printed tablets. Int J Pharm 2015c;494:657e663; Goyanes A, Buanz AB, Hatton GB, Gaisford S, Basit AW. 3D printing of modified-release aminosalicylate (4-ASA and 5-ASA) tablets. Eur J Pharm Biopharm 2015a;89:157e162; Goyanes A, Wang J, Buanz A, Martínez-Pacheco R, Telford R, Gaisford S, Basit AW. 3D printing of medicines: engineering novel oral devices with unique design and drug release characteristics. Mol Pharm 2015d;12:4077e4084.

Infill is the process by which the print head will print an outer shell of the shape of the part and the inside of this shell is filled in with a particular pattern to accommodate a predefined volume percentage. The material that is printing between the outer shell is termed “infill” and can be controlled through software to define both the geometry of the infill material as well as the amount of infill. In addition to their use in solid filament as the starting material for extrusion-based 3DP, viscous pastes and UV curable polymers have been shown to be viable feedstocks for extrusion-based 3DP of active dosage forms [46,47,49]. Preparing these starting materials as shown in Fig. 2.11 requires less process development as compared to an extrusion-based approach; however, these dosage forms typically

require postprocessing, such as drying or active thermal curing, and the mechanical properties for the resulting dosage product have not been investigated thoroughly. With both of these approaches, API chemical and/or physical stability may be compromised. These paste formulations have been printed using similar equipment to an FDM printer, except the hot end is replaced with a closed shot canister. Using this approach, HPMC and polyacrylic acid (Carbopol 974P) [46], HPMC and lactose [47], and HPMC hydroalcoholic gels [49] have been printed. Notably, this approach has been used for polypills [47,49], which are single oral dosage forms that contain three or more isolated volumes each containing a different active ingredient. While paste formulations open doors to more material choices, this approach typically requires

36

2. Opportunities and challenges of 3D-printed pharmaceutical dosage forms

FIGURE 2.11 (i) Schematic diagrams of (A) the dispersion technique of hypromellose (HPMC) 2910 powder and (B) formulation of HPMC hydroalcoholic gel [46]. (ii) Photograph of a RegenHU 3D printer (left) RegenHU Switzerland (regnhu,com), and image of a multiactive tablet (right) (10.45 mm [height], 6 mm [radius]) composed of a captopril osmotic pump compartment (bottom), and nifedipine (hole I) and glipizide (hole II) sustained release compartments (top) and joining layer (middle).

subsequent steps such as overnight drying of the print to remove any solvent or water from the dosage form for long-term physical stability, and it is unclear at this time how the mechanical robustness of paste-printed dosage forms will endure secondary packaging and user handling. These are existing examples of implementing 3DP technology into rapid prototype release

rates using different strategies, largely focused on maintaining a similar material feedstock and using creative printing parameters to generate various releases. With all the following examples, at least one solid filament material is preprocessed to contain API. The extrusion of filaments or pastes has been used to manufacture what are termed core/shell tablets, where

5. Pharmaceutical applications for drug delivery

the outer shell’s thickness is varied, and has demonstrated the generation of distinct release rates. Core/shell tablets have been manufactured by using a second API-containing material [8] or a placebo material with the intent to mimic enteric-coated tablets [9,10], and have demonstrated the agility of 3DP to change the onset of the release of the core of the dosage form by as much as 2 h in vitro using the same material feedstock. While these strategies have been demonstrated to provide a software tuning knob for release rate manipulation while maintaining a constant material feedstock, all of these strategies rely on HME formulation of a printable filament for each API. Developing process conditions to incorporate API into an excipient-based solid filament is usually not trivial [11e14], and these filament processing developments add to the product development burden, reducing the rapid prototyping advantage 3DP brings to the table for early drug screenings. Fina et al. [52] presented the first published work to utilize SLS for the production of oral dosage forms using two thermoplastic pharmaceutical-grade polymers, Kollicoat IR (75% polyvinyl alcohol and 25% PEG copolymer) and Eudragit L100-55 (50% methacrylic acid and 50% ethyl acrylate copolymer), with immediate and modified release characteristics. For this process to achieve printability and aid in the sintering process, pharmaceutical-grade silicate and oxide-based pigments are added to improve laser energy absorption and dissipation. In general, SLSprinted dosage forms have poorer surface quality and higher porosity as shown in the example from [52] (Fig. 2.12A). Control of the release rate of the SLS dosage forms based on the research thus far is governed more by the thermoplastic material than by the printing conditions as seen in Fig. 2.12B.

37

5.2 Paste/gel extrusion-based technologies A unique approach that attempts to incorporate both filament-based and paste/gel extrusion-based technologies has been developed by Smith et al. [50,51]. The aim of their work was to take advantage of the printability of pharmaceutically acceptable polymers like PLA and PVA while limiting the processing of API to similar approaches shown earlier for paste, liquids, and gel-based formulations. They developed a single-step FDM 3DP process to manufacture thin-walled drug-free capsules, which can be filled with dry or liquid drug product formulations. Drug release from these systems is governed by the combined dissolution of the FDM capsule “shell” and the dosage form encapsulated in these shells. To prepare the shells, the 3D printer files (extension “.gcode”) were modified by creating discrete zones, so-called “zoning process,” with individual print parameters. Their work clearly shows several unique aspects of the difficulty in 3DP quality dosage forms that are elegant and water tight. The geometry of the dosage form requires a design that is specific to the 3DP process, breaking from the more traditional shapes to account for the physics of 3DP. In their work they highlight the need to redesign the shape with different angles (so-called zoning) using software that is commonly available to the public. Fig. 2.13 shows different colors within the dosage form to show where FDM thermal and mechanical process conditions are purposely changed to improve the quality of the final printed dosage form. It is well known that the speed of FDM 3D printers is not particularly fast as compared to traditional dosage form manufacturing where a rotary tablet press can accommodate on the order of 1,000,000 tablets per hour. A 3D printer

38

FIGURE 2.12

2. Opportunities and challenges of 3D-printed pharmaceutical dosage forms

(A): Scanning electron microscopy images of the selective laser sintering of printlet vertical sections. On the top from left to right, Kollicoat IR K5, K20, and K35. On the bottom from left to right, Eudragit L100-55 E5, E20, and E35, where 5, 20, and 35 represent the wt% of paracetamol used as a model active pharmaceutical ingredient. (B) Drug dissolution from Eudragit SLS printlets. Adapted from Fina F, Goyanes A, Gaisford S, Basit AW. Selective laser sintering (SLS) 3D printing of medicines. Int J Pharm 2017;529:285e293.

39

6. Conclusions

FIGURE 2.13 (A) Computer-aided design representation of a single-walled capsule with varying colors depicting the different print zones. (B, C) Top and side optical views, respectively, of polyvinyl alcohol (PVA) capsules printed on an Ultimaker 2þ at 60 mm/s with no zoning, and (D, E) with zoning. (F, G) Top and side optical views, respectively, of PVA capsules printed on a Hyrel 3D System 30M at 25 mm/s with no zoning, and (H, I) with zoning.

may have the ability to manufacture approximately 10e100 dosage forms per hour depending on many printing conditions. Controlling features that balance print speed and quality are nozzle

FIGURE 2.14 Graph of flow rate versus maximum sustainable extrusion temperature on a Hyrel 3D System 30M printer. The red region above data points indicates conditions at which the nozzle will clog due to polyvinyl alcohol degradation. The red region in the bottom right corner indicates poor print conditions resulting in poor mechanical properties of the printed capsule, or nonflow through the nozzle orifice. The green region indicates a stable print condition with better mechanical properties.

diameter, layer height, and material flow rate (Fig. 2.14). Purposeful studies to optimize printing conditions are required to maximize dosage form throughput using FDM print technology that is available today. Smith et al. have also evaluated these conditions for dosage form quality and these are copied here (Fig. 2.15). As stated earlier, a unique ability of 3DP is in the discrete control of one dosage form to create structures that control release rates. As shown in Fig. 2.16, using the software zoning process and knowledge of erosion rates of PVA, dosage forms can be designed to release at different regions in the gastrointestinal tract.

6. Conclusions 3DP has shown impressive R&D potential and commercial value in industries such as automotive, aerospace, and medical devices where product optimization and customization have had a significant benefit. In the pharmaceutical industry, 3DP offers a similar promise to rapid prototype dosage forms in a preclinical and clinical setting and significant future potential in commercial patient centric dosing. Additionally, pharmaceutical 3DP may evolve into manufacturing nodes at doctors’ offices and local pharmacies. Addressing the known material and technology deficiencies will make this future state possible. Utilization of 3DP technologies requires a unique presentation of material for the required phase transformation. For example, the need to have biopharmaceutically acceptable polymers in a filament form for FDM printing is not possible for all polymers because of the required technical specifications (e.g., mechanical strength and thermal degradation) that allow for successful printing conditions. The material challenges for successful SLS printing are governed by the ability to process thermoplastic materials into highly flowable (i.e., spherical),

40

2. Opportunities and challenges of 3D-printed pharmaceutical dosage forms

FIGURE 2.15 X-ray computed tomography reconstruction images of capsules with various print conditions on a Hyrel 3D System 30M printer, cropped to see the internal wall structure and shape. Adapted from Smith D, Kapoor Y, Klinzing G, Procopio A. Pharmaceutical 3D printing: design and qualification of a single step print and fill capsule. Int J Pharm 2018a;544(2018):21e30; Smith D, Kapoor Y, Hermans A, Nofsinger R, Kesisoglou F, Gustafson T, Procopio A. 3D printed capsules for quantitative regional absorption studies in the GI tract. Int J Pharm 550;2018b:418e28.

unimodal particles. In SLA, residual monomer/ oligomer and free radical population in the printed dosage form are of primary concern for patient safety. Overcoming this challenge while defining a high-quality printable SLA formulation still needs a solution. So far, the pharmaceutical industry has adapted 3DP technologies that have existed previously and were built to handle engineering materials for the purposes of rapid prototyping. As discussed earlier, researchers have had to accommodate and transform materials to be

able to print using 3D technologies that were not designed for pharmaceutical materials. One example that was described in this chapter focused on the need for strong interlayer adhesion of more than one thermoplastic pharmaceutical material in FDM for oral-controlled delivery. This particular challenge is because of the low Tg of pharmaceutical materials as compared with engineering materials as well as material interfacial incompatibility. 3DP offers a paradigm change for our industry across manufacturing, regulatory, and

6. Conclusions

41

FIGURE 2.16

(A) Computer-aided design images of 3-wall and 7-wall polyvinyl alcohol capsules, (B) burst (green [dark gray in printed version] bars) and 85% release (blue [dark gray in printed version] patterned bars) graphs in vitro dissolution for 3-wall and 7-wall powder-A filled capsules, (C) in vivo drug concentrations in blood in dogs for the 50 mg immediate release (IR) tablet and 40 mg 3-wall and 7-wall powder-A filled capsules, and (D) enlarged inset of (C) for the first 5 h.

quality functions. As of now, 3DP is not considered as a mass production technology due to limitations in hardware and material and has been used for products requiring moderate throughput. However, should the pharmaceutical industry look to leverage distributed manufacturing and personalized medicine, 3DP is poised to disrupt traditional pharmaceutical mass production. From a quality point of view, the current mode of releasing pharmaceutical

product relies on the testing of a statistically relevant subset of the aforementioned massproduced product, whereas 3DP layered with process analytical technology has the potential to offer an advantage of in-depth analytical prosecution for every dosage form being produced. Due to the intrinsic layer-by-layer construction of the 3D-printed dosage form, process analytical technologies can evaluate these layers during production, which is not

42

2. Opportunities and challenges of 3D-printed pharmaceutical dosage forms

capable with traditional pharmaceutical processing. As discussed earlier, because of the novelty of this technology, regulatory guidance does not exist for drug products but as industry and academicians push forward R&D into commercial space, we anticipate alignment and regulation as has happened historically for other process technologies. The primary advantage that is offered and frequently discussed by 3DP is with customization. To this end, one version of the pharmaceutical industry future looks to address patient centric dosing in terms of combining multiple medications and controlling for drug release rates that are tuned to maximize efficacy and minimize side effects based on a patient’s phenotype and genotype. Traditional pharmaceutical process technologies do not offer this level of per dosage form customization and 3DP is on the verge of disrupting this industry to provide dosage forms that accomplish these goals. The key to achieving this relies on the repurposing of traditional materials and development of novel materials that provide the level of quality needed for meeting drug product specifications. Material and 3DP vendors and academic and industrial research units have shown significant progress for pushing the technology for pharmaceutical applications and the authors believe that this trend will continue in the foreseeable future.

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[31] Konta AA, Pina Garcia M, Serrano DR. Personalized 3D printed medicines: which techniques and polymers are more successful? Bioengineering 2017;4:79. https://doi:10.3390/bioengineering4040079. [32] Fuenmayor E, Forde M, Healy AV, Devine D,M, Lyons JG, McConville C, Major I. Material considerations for fused-filament fabrication of solid dosage forms. Pharmaceutics 2018;10:44. https://doi.org/ 10.3390/pharmaceutics10020044. [33] Solanki NG, Tahsin M, Shah AV, Serajuddin ATM. Formulation of 3D printed tablet for rapid drug release by fused deposition modeling: screening polymers for drug release, drug-polymer miscibility and printability. J Pharm Sci 2018;107:390e401. [34] American Chemical Council- Introduction to Polyurethanes: Thermoplastic Polyurethanes. https://polyure thane.americanchemistry.com/Introduction-to Polyurethanes/Applications/Thermoplastic-Polyurethane//. [35] Tan KD, Maniruzzanan M, Nokhodchi A. Advanced pharmaceutical applications of hot-melt extrusion coupled with Fused deposition modelling (FDM) 3D printing with personalized drug delivery. Pharmaceutics 2018;10:203. https://doi.org/ 10.3390/pharmaceutics10040203. [36] Hou MM. 3D printed filaments: what’s the deal with ULTEM and PEEK? 2017. https://www.engineering. com/3DPrinting/3DPrintingArticles/ArticleID/ 14465/3D-Printing-Filaments-Whats-the-Deal-withULTEM-and-PEEK.aspx. [37] Wu WZ, Geng P, Zhao Y, Rosen DW, Zhang HB. Manufacture and thermal deformation analysis of semicrystalline polymer polyether ether ketone by 3D printing. Mater Res Innov 2014;18. https:// doi.org/10.1179/1432891714Z.000000000898. [38] Kim SH, Yeon YK, Lee JM, Chao JR, Lee YJ, Seo YB, Lee JS. Precisely printable and biocompatible silk fibroin bioink for digital light processing 3D printing. Sang Jin Lee James J. Yoo 2018;3(17). https://doi.org/10.1038/s41467-018-03759-y. [39] Bloomquist CJ, Mecham MB, Paradzinsky MD, Janusziewicz R, Warner SB, Luft JC, DeSimone JM. Controlling release from 3D printed medical devices using CLIP and drug-loaded liquid resins. August 2017 J Control Release 2018;278:9e23. https:// doi.org/10.1016/j.jconrel.2018.03.026. [40] Tumbleston JR, Shirvanyants D, Ermoshkin N, Janusziewicz R, Johnson AR, Kelly D, Desimone JM. Continuous liquid interface production of 3D objects. Science 2015;347(6228):635e9. [40a] du Plessis A, le Roux SG, Steyn F. Quality investigation of 3D printer filament using laboratory X-ray tomography. 3D print, Additive Manuf 2016;3:262e7.

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[40b] Markl D, Zeitler JA, Rasch C, Michaelsen MH, M€ ullertz A, Rantanen J, Rades T, Bøtker J. Analysis of 3D prints by X-ray computed microtomography and terahertz pulsed imaging. Pharm Res 2017;34: 1037e52. [41] Melocchi A, Parietti F, Loreti G, Maroni A, Gazzaniga A, Zema L. 3D printing by fused deposition modeling (FDM) of a swellable/erodible capsular device for oral pulsatile release of drugs. J Drug Deliv Sci Technol 2015;30:360e7. [41a] Okwuosa TC, Pereira BC, Arafat B, Cieszynska M, Isreb A, Alhnan MA. Fabricating a shell-core delayed release tablet using dual FDM 3D printing for patientcentred therapy. Pharm Res 2017;34:427e37. [41b] Okwuosa TC, Stefaniak D, Arafat B, Isreb A, Wan KW, Alhnan MA. A lower temperature FDM 3D printing for the manufacture of patient-specific immediate release tablets. Pharm Res 2016;33:2704e12. [42] Goyanes A, Buanz AB, Basit AW, Gaisford S. Fusedfilament 3D printing (3DP) for fabrication of tablets. Int J Pharm 2014;476:88e92. [43] Goyanes A, Buanz AB, Hatton GB, Gaisford S, Basit AW. 3D printing of modified-release aminosalicylate (4-ASA and 5-ASA) tablets. Eur J Pharm Biopharm 2015a;89:157e62. [44] Goyanes A, Wang J, Buanz A, Martínez-Pacheco R, Telford R, Gaisford S, Basit AW. 3D printing of medicines: engineering novel oral devices with unique design and drug release characteristics. Mol Pharm 2015d;12:4077e84. [44a] Kempin W, Franz C, Koster L-C, Schneider F, Bogdahn M, Weitschies W, Seidlitz A. Assessment of different polymers and drug loads for fused deposition modeling of drug loaded implants. Eur J Pharm Biopharm 2017;115:84e93. [45] Arafat B, Qinna N, Cieszynska M, Forbes RT, Alhnan MA. Tailored on demand anti-coagulant dosing: an in vitro and in vivo evaluation of 3D printed purpose-designed oral dosage forms. Eur J Pharm Biopharm 2018a;128:282e9. [46] Khaled SA, Burley JC, Alexander MR, Roberts CJ. Desktop 3D printing of controlled release pharmaceutical bilayer tablets. Int J Pharm 2014;461:105e11. [47] Khaled SA, Burley JC, Alexander MR, Yang J, Roberts CJ. 3D printing of five-in-one dose combination polypill with defined immediate and sustained release profiles. J Control Release 2015a;217:308e14. [48] Melocchi A, Parietti F, Maroni A, Foppoli A, Gazzaniga A, Zema L. Hot-melt extruded filaments based on pharmaceutical grade polymers for 3D printing by fused deposition modeling. Int J Pharm 2016. [49] Khaled SA, Burley JC, Alexander MR, Yang J, Roberts CJ. 3D printing of tablets containing multiple drugs with defined release profiles. Int J Pharm 2015b; 494:643e50.

[50] Smith D, Kapoor Y, Klinzing G, Procopio A. Pharmaceutical 3D printing: design and qualification of a single step print and fill capsule. Int J Pharm 2018a; 544(2018):21e30. [51] Smith D, Kapoor Y, Hermans A, Nofsinger R, Kesisoglou F, Gustafson T, Procopio A. 3D printed capsules for quantitative regional absorption studies in the GI tract. Int J Pharm 2018b;550:418e28. [52] Fina F, Madla CM, Goyanes A, Zhang J, Gaisford S, Basit AW. Fabricating 3D printed orally disintegrating printlets using selective laser sintering. Int J Pharm 2018;541:101e7. [53] Nippon Gohsei. MelfilÔ product brochure. 2016. http://www.nippon-gohsei.com/cache/downloads/7m5hyx0hc1wkc08cg8k40occ4/MELFIL% 20Brochure%202016%20English.pdf.

Further reading Laulicht B, Tripathi A, Schlageter V, Kucera P, Mathiowitz E. Understanding gastric forces calculated from highresolution pill tracking. Proc Natl Acad Sci 2010;107: 8201e6. € H€allgren R, Knutson L, Ryde M, Lennern€as H, Ahrenstedt O, Paalzow LK. Regional jejunal perfusion, a new in vivo approach to study oral drug absorption in man. Pharm Res 1992;9:1243e51. Maroni A, Melocchi A, Parietti F, Foppoli A, Zema L, Gazzaniga A. 3D printed multi-compartment capsular devices for two-pulse oral drug delivery. J Control Release 2017;268:10e8. Martinez PR, Goyanes A, Basit AW, Gaisford S. Influence of geometry on the drug release profiles of stereolithographic (SLA) 3D-printed tablets. AAPS PharmSciTech 2018:1e7. Melocchi A, Parietti F, Maccagnan S, Ortenzi MA, Antenucci S, Briatico-Vangosa F, Maroni A, Gazzaniga A, Zema L. Industrial development of a 3Dprinted nutraceutical delivery platform in the form of a multicompartment HPC capsule. AAPS PharmSciTech 2018:1e12. Okwuosa TC, Soares C, Gollwitzer V, Habashy R, Timmins P, Alhnan MA. On demand manufacturing of patient-specific liquid capsules via co-ordinated 3D printing and liquid dispensing. Eur J Pharm Sci 2018;118: 134e43. Sun Q, Rizvi G, Bellehumeur C, Gu P. Effect of processing conditions on the bonding quality of FDM polymer filaments. Rapid Prototyp J 2008;14:72e80. Wang J, Goyanes A, Gaisford S, Basit AW. Stereolithographic (SLA) 3D printing of oral modified-release dosage forms. Int J Pharm 2016;503:207e12.

C H A P T E R

3 Marketing authorization and licensing of medicinal products in EU: Regulatory aspects Muhaned Al-Hindawi OnTarget Pharma Consultancy Limited, New Malden, Surrey, United Kingdom

1. Introduction

and the drug product’s release in the market. Also, they would cover the indication(s) approved, side effects reported, legal status and presentations, as well as follow-up issues while in the market. From the applicant perspective, the procedures followed and compliance with the requirements are crucial, dictating the strategy of marketing of the medicinal product in the concerned Member States and level of penetration envisaged. In this chapter, the governing bodies in the EU and their role, the legal framework, and rules regulating the entrance of the medicinal product and licensing in the EU is explained. Whilst focus on the human medicinal products will be made; however, and wherever appropriate the committees and groups that govern the licensing of veterinary medicines will be mentioned. In general, the same documents may apply for both types of medicinal products unless they are specifically mentioned. While covering the main concepts and requirements for licensing and marketing of medicinal products in the EU, discussion of licensing

The EU market represented by its 27 Member States (plus Norway, Iceland, and Liechtenstein) and possibly the United Kingdom (pending negotiations on Brexit) is very large in size and pharmaceutical companies from around the world find it very lucrative to penetrate, observing the rules governing licensing medicinal products in the EU. From EU perspectives, it is imperative that these medicinal products are of the quality and standard to be considered safe and efficacious from the time of manufacture and over their shelf life. Also, it is imperative that medicinal products are prescribed and dispensed in line with the indication(s) approved along with their safety profiles being transparent to the public and consumers. These rules and guidelines would cover licensing and regulation of manufacturing sites, quality of the drug substance as an active ingredient, quality of the drug product manufactured,

Drug Delivery Trends https://doi.org/10.1016/B978-0-12-817870-6.00003-1

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© 2020 Elsevier Inc. All rights reserved.

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3. Marketing authorization and licensing of medicinal products in EU: Regulatory aspects

medicinal products containing chemical entities of the drug substance is primarily made, but does not cover biologicals. In most cases, different rules would apply, which are beyond the aim of this chapter. Furthermore, pharmacovigilance regulations and guidelines, though part of the licensing requirements, are beyond the aim of this chapter and will not be covered. Procedures for referrals and tribunals, when no consensus among all concerned Member States involved in the application can be agreed in the initial process of assessment and timelines, are covered. Also, the role and responsibility of the marketing authorization holder (MAH) to ensure compliance with the rules in effect at the time of submission and throughout the lifecycle of the product while it is licensed will be explained. In addition to the EU guidelines, compliance with national rules in drawing the strategy of marketing and sale of the medicinal product in the concerned Member State would have to be carefully considered. In this respect it is important to highlight that although all EU Member States are obliged to abide by EU rules, they still have their own national rules that need to be considered and a difference in the requirements between these two rules is possible. As an aid for better understanding, hyperlinks to the main websites are given when possible.

2. European Union legal framework, hierarchy, and committees In this section the legal entities and committees of the European Medicines Agency (EMA), the hierarchy within the EU, and the process of decision-making are explained. This is of importance due to direct involvement of the EMA (via its different committees) in drawing the policy of the Agency, governing the process of marketing authorization of medicinal products in the EU, publishing guidelines, as well as reviewing and

deciding on referred cases when synonymous decisions within the different Member States cannot be reached. The following is the hierarchy of the EU and linkage to the EMA as depicted in Fig. 3.1.

2.1 The European Union The EU is a politico-economic union of 27 (after Brexit) Member States that are located primarily in Europe. The EU operates through a system of supranational institutions and intergovernmental-negotiated decisions by the Member States. It has an area of 4,475,757 km2 (1,728,099 sq mi) and an estimated population of over 510 million. The EU has developed an internal single market through a standardized system of laws that apply in all Member States.

2.2 The European commission [1] This is the EU’s executive arm. It makes decisions on the Union’s political and strategic direction. The Commission is steered by a group of 27 (after Brexit) Commissioners, known as “the college.” Together they make decisions on the Commission’s political and strategic direction.

2.3 Departments and agencies [2] The Commission is organized into policy departments, known as Directorates-General (DGs), which are responsible for different policy areas. DGs develop, implement, and manage EU policy, law, and funding programs. In addition, service departments deal with particular administrative issues. Executive agencies manage programs set up by the Commission.

2.4 Consumers, health, agriculture and food executive agency [3] This executive agency of the Commission manages EU programs on consumer rights, health, agriculture, and safe food.

2. European Union legal framework, hierarchy, and committees

47

The European Union (EU) A polical –economic union of 27 (aer Brexit) members states that are located primarily in Europe.

The European commission (EC) The EU’s execuve arm. It takes decision on the union polical & strategic direcon.

Departments & Agencies (DGs) Develop, implement and manage EU policy, law, and funding programmes. Execuve agencies manage programmes set up by the Commission.

European Medicines Agency EMA Set up by EC Regulaon No. 2309/93 as the European Agency for the Evaluaon of Medicinal Products (EMEA) and renamed by EC Regulaon No. 726/2004 to the European Medicines Agency (EMA).

FIGURE 3.1

Hierarchy of the European Union and linkage to the European Medicines Agency.

2.5 Health and food safety department [4] This Commission department is responsible for EU policy on food safety and health and for monitoring the implementation of related laws.

2.6 European medicines agency [5] The EMA was set up by European Commission (EC) Regulation No. 2309/93 as the European Agency for the Evaluation of Medicinal Products and renamed by EC Regulation No. 726/2004 to the European Medicines Agency. The EMA is a decentralized agency of the European Union. It began operating in 1995 relocated from London to Amsterdam/The Netherlands on March 29, 2019. The Agency is responsible for the scientific evaluation, supervision, and safety monitoring of medicines in the EU.

The EMA protects public and animal health in the EU Member States, as well as the countries of the European Economic Area (EEA), by ensuring that all medicines available on the EU market are safe, effective, and of high quality. The EMA serves a market of over 500 million people living in the EU The organizational plan of the EMA is presented in Fig. 3.2. The EMA has seven scientific committees and several working parties and related groups, which conduct the scientific work of the Agency. The working parties and groups are made up of members who have expertise in a particular scientific field, selected from the list of European experts maintained by the Agency. Members are given tasks associated with the scientific evaluation of marketing authorization applications or drafting and revision of scientific guidance documents.

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3. Marketing authorization and licensing of medicinal products in EU: Regulatory aspects

EMA

Co-ordinaon groups

Mutual Recognion & Decentralised Procedures Human (CMDh)

Commiee for Medicinal Products for Human USE (CHMP)

Pharmacovigilance Risk Assessment Commiee (PRAC)

Mutual Recognion & Decentralised Procedure Veterinary (CMDv)

Commiee for Medicinal Products for Veterinary Use (CVMP)

Commiee for Orphan Medicinal Products (COMP)

Commiee on Herbal Medicinal Products (HMPC)

Commiee for Advanced Therapies (CAT)

Paediatric Commiee (PDCO)

FIGURE 3.2 Hierarchy of the European Medicines Agency whereby each committee has a working party.

The following is a brief description of each of the EMA committees, their roles and responsibilities as well as standing working parties linked to each committee. For more about other committees-associated groups, readers are advised to visit the main website of the EMA/committees. 2.6.1 Committee for medicinal products for human use [6] This is the EMA’s committee responsible for human medicines. 2.6.1.1 Role

The Committee for Medicinal Products for Human Use (CHMP) plays a vital role in the authorization of medicines in the EU. In the centralized procedure, the CHMP is responsible for: • Conducting the initial assessment of EU-wide marketing authorization applications

• Assessing modifications or extensions (“variations”) to an existing marketing authorization • Considering the recommendations of the Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) on the safety of medicines on the market and when necessary recommending to the EC changes to a medicine’s marketing authorization, or its suspension or withdrawal from the market • Evaluating medicines authorized at national level referred to the EMA for a harmonized position across the EU. For more information, see union referral procedures discussed in section 2 of this chapter The current CHMP standing working parties are: • • • • • •

Healthcare Professionals’ Working Party Biologics Working Party Patients’ and Consumers’ Working Party Quality Working Party Safety Working Party Scientific Advice Working Party

2. European Union legal framework, hierarchy, and committees

The CHMP is further supported by the work of the Good Manufacturing Practice, Good Clinical Practice, and Good Laboratory Practice Inspection Services Groups. Information on their role is available on the EMA website.

2.6.3 Committee for medicinal products for veterinary use [8]

2.6.2 Pharmacovigilance risk assessment committee [7]

2.6.3.1 Role

This is the EMA’s committee responsible for assessing and monitoring the safety of human medicines. The PRAC was formally established in line with the pharmacovigilance legislation, which came into effect in 2012 to help strengthen the safety monitoring of medicines across Europe. 2.6.2.1 Role

The PRAC is responsible for assessing all aspects of risk management of human medicines, including: • The detection, assessment, minimization, and communication of the risk of adverse reactions, while taking the therapeutic effect of the medicine into account; • Design and evaluation of post-authorization safety studies; • Pharmacovigilance audit. The PRAC provides recommendations on questions on pharmacovigilance and risk management systems, including the monitoring of their effectiveness, to the: • CHMP for centrally authorized medicines and referral procedures; • Coordination Group for Mutual Recognition and Decentralised ProceduresdHuman (CMDh) on the use of a medicine in Member States; • The EMA secretariat, Management Board, and EC, as applicable. By virtue of the nature of the PRAC, there are no working parties or groups attached to it.

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This is the EMA’s committee responsible for veterinary medicines, established in line with Regulation (EC) No. 726/2004.

The Committee for Medicinal Products for Veterinary Use (CVMP) plays a vital role in the authorization of veterinary medicines in the EU. In the centralized procedure, the CVMP is responsible for: • Conducting the initial assessment of EU-wide marketing authorization applications; • Postauthorization and maintenance activities, including the assessment of any modifications or extensions (“variations”) to an existing marketing authorization; • Safety monitoring of veterinary medicines on the market and when necessary recommending to the EC changes to a medicine’s marketing authorization, or its suspension or withdrawal from the market. For more information, see veterinary pharmacovigilance given in the EMA website. The CVMP also evaluates veterinary medicines authorized at national level referred to the EMA for a harmonized position across the EU. For more information, see veterinary referral procedures given in the EMA website. The CVMP recommends safe limits for residues of veterinary medicines used in foodproducing animals and biocidal products used in animal husbandry for the establishment of maximum residue limits by the EC. In addition, the CVMP and its working parties contribute to the development of veterinary medicines and medicine regulation by: • Providing scientific advice to companies researching and developing new veterinary medicines;

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3. Marketing authorization and licensing of medicinal products in EU: Regulatory aspects

• Preparing scientific guidelines and regulatory guidance to help pharmaceutical companies prepare marketing authorization applications for veterinary medicines; • Cooperating with international partners on the harmonization of regulatory requirements. 2.6.3.1.1 Assessments

The CVMP’s assessments are based on a comprehensive scientific evaluation of data. They determine whether the medicine meets the necessary quality, safety, and efficacy requirements and that is has a positive risk/benefit balance in favor of the animal population they are intended for. A peer-review system safeguards the accuracy and validity of the opinions of the committee. The current CVMP working parties are: • Antimicrobials Working Party • Efficacy Working Party • Environmental Risk Assessment Working Party • Immunologicals Working Party • Quality Working Party • Pharmacovigilance Working Party • Safety Working Party • Scientific Advice Working Party The CVMP is further supported by the work of the Good Manufacturing Practice Inspection Services Group. Information on its role is available on the EMA website. 2.6.4 Committee for Orphan Medicinal Products [9] This is the EMA’s committee responsible for recommending orphan designation of medicines for rare diseases, established in 2000, in line with Regulation (EC) No. 141/2000. 2.6.4.1 Role

The Committee for Orphan Medicinal Products (COMP) is responsible for evaluating

applications for orphan designation for human use. This designation is for medicines to be developed for the diagnosis, prevention, or treatment of rare diseases that are life threatening or very serious. In the EU, a disease is defined as rare if it affects fewer than 5 in 10,000 people across the EU. The EC decides whether to grant an orphan designation for the medicine based on the COMP’s opinion. An orphan designation allows a pharmaceutical company to benefit from incentives from the EU, such as reduced fees and protection from competition once the medicine is placed on the market. The COMP also advises and assists the EC on matters related to orphan medicines, including: • Developing and establishing an EU-wide policy; • Drawing up detailed guidelines; • Liaising internationally. The current COMP working party is: Patients’ and Consumers’ Working Party. 2.6.5 Committee on herbal medicinal products [10] This is the EMA‘s committee responsible for compiling and assessing scientific data on herbal substances, preparations, and combinations to support the harmonization of the European market. The Committee on Herbal Medicinal Products (HMPC) replaced the Committee for Proprietary Medicinal Products’ Working Party on Herbal Medicinal Products in September 2004. The Committee was established in accordance with Regulation (EC) No. 726/2004 and the Herbal Directive, which introduced a simplified registration procedure for traditional herbal medicinal products in EU Member States. The HMPC is composed of scientific experts in the field of herbal medicines.

2. European Union legal framework, hierarchy, and committees

2.6.5.1 Role

The HMPC prepares the Agency’s opinions on herbal substances and preparations, along with information on recommended uses and safe conditions. This work supports the harmonization of the European market: national competent authorities are able to refer to one unique set of information on an herbal substance or preparation when evaluating marketing applications for herbal medicines. To support EU Member States, the HMPC focuses on two main tasks: • Establishing EU monographs covering the therapeutic uses and safe conditions of well-established and/or traditional use for herbal substances and preparations; • Drafting an EU list of herbal substances, preparations, and combinations thereof for use in traditional herbal medicinal products. The HMPC and its working parties and other groups also: • Prepare scientific guidelines and regulatory guidance to help companies prepare marketing authorization and registration applications for herbal medicines; • Prepare opinions on questions referred to the EMA by the national competent authorities regarding the period and evidence of safe use for traditional herbal medicinal products; • Cooperate with the European Directorate for the Quality of Medicines and Healthcare on European Pharmacopoeia standards and EMA guidance on the quality of herbal medicines; • Coordinate with other scientific committees at the Agency on the regulation and safe use of herbal medicines; • Provide scientific and regulatory support to companies researching and developing herbal medicines;

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• Interact with interested parties; • Provide advice and training to herbal assessors of national competent authorities; • Cooperate with international partners on the harmonization of regulatory requirements. The current HMPC working parties are: • Working Party on European Union Monographs and European Union List • Patients’ and Consumers’ Working Party The HMPC is further supported by the work of the Good Manufacturing Practice Inspection Services Group. Information on its role is available on the EMA website. 2.6.6 Committee for advanced therapies [11] This is the EMA’s committee responsible for assessing the quality, safety, and efficacy of advanced therapy medicinal products (ATMPs) and following scientific developments in the field. It was established in accordance with Regulation (EC) No. 1394/2007 on ATMPs as a multidisciplinary committee, gathering some of the best available experts in Europe. 2.6.6.1 Role

The committee’s main responsibility is to prepare a draft opinion on each ATMP application submitted to the EMA before the CHMP adopts a final opinion on the marketing authorization of the medicine concerned. At the request of the EMA’s Executive Director or the EC, the Committee for Advanced Therapies (CAT) can also draw up an opinion on any scientific matter relating to ATMPs. The CAT also: • Participates in certifying quality and nonclinical data for small and medium-sized enterprises developing ATMPs;

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• Participates in providing scientific recommendations on the classification of ATMPs; • Contributes to scientific advice in cooperation with the Scientific Advice Working Party; • Takes part in any procedure delivering advice on the conduct of efficacy follow-up, pharmacovigilance, or risk-management systems for ATMPs; • Advises the CHMP on any medicinal product that may require expertise in ATMPs for the evaluation of its quality, safety, or efficacy; • Assists scientifically in developing any documents relating to the objectives of the Regulation on ATMPs; • Provides scientific expertise and advice for any Community initiative related to the development of innovative medicines and therapies that requires expertise on ATMPs; • Supports the work programs of the CHMP working parties. The CAT’s work plan includes developing guidance documents, contributing to crosscommittee projects, work on simplification of procedures and requirements for ATMPs, training for assessors, and organizing scientific workshops. The current CAT associated group is: • EMA/CAT and Medical Devices’ Notified Body Collaboration Group 2.6.7 Paediatric committee [12] This is the EMA’s scientific committee responsible for activities on medicines for children and to support the development of such medicines in the EU by providing scientific expertise and defining paediatric needs. The Paediatric Committee (PDCO) was established in line with the Paediatric Regulation, which came into effect in 2007, to improve the health of children in Europe by facilitating the development and availability of medicines for children aged 0e17 years.

2.6.7.1 Role

The PDCO’s main role is to assess the content of paediatric investigation plans (PIPs), which determine the studies that companies must carry out in children when developing a medicine. This includes assessing applications for a full or partial waiver and for deferrals. The committee’s other roles include: • Assessing data generated in accordance with agreed PIPs; • Adopting opinions on the quality, safety, or efficacy of a medicine for use in the paediatric population, at the request of the CHMP or a medicines regulatory authority in an EU Member State. The PDCO can give an opinion if the data have been generated in accordance with an agreed PIP; • Advising Member States on the content and format of data to be collected through surveys on the uses of medicines in children; • Advising and supporting the development of the European Network of Paediatric Research at the EMA; • Providing advice on questions on paediatric medicines, at the request of the Agency’s Executive Director or the EC; • Establishing and regularly updating an inventory of paediatric medicine needs; • Advising the Agency and the EC on how to communicate the arrangements available for conducting research into paediatric medicines. The PDCO is not responsible for marketing authorization applications for medicines for use in children, which is in the remit of the CHMP. The current PDCO working groups are: • Formulation Working Group • Non-clinical Working Group • Modelling and Simulation Working Group

3. Legal framework for licensing medicines for human use in the EU

2.7 Coordination groups 2.7.1 Coordination group for mutual recognition and decentralised proceduresdhuman [13] CMDh was set up in 2005. It replaced the informal Mutual Recognition Facilitation Group. The CMDh examines questions relating to the marketing authorization of human medicines in two or more EU Member States in accordance with the mutual recognition or the decentralized procedures and questions concerning variations of these marketing authorizations. If there is disagreement between Member States during the assessment of the submitted data based on the grounds of a potential serious risk to public health, the CMDh considers the matter and strives to reach an agreement within 60 days. If this is not possible, the Member State responsible for the product brings the case to the attention of the CHMP for arbitration. The CMDh examines questions concerning the safety of noncentrally authorized medicines marketed in the EU where centrally authorized products are not affected. This includes adopting a CMDh position on safety-related EU referral procedures, taking account of the recommendations of the PRAC. Each year the CMDh identifies a list of medicines for which harmonized product information should be drawn up, to promote the harmonization of marketing authorizations across the EU. More information about the CMDh activities, including a complete overview of its functions and tasks, can be found on the CMDh website. 2.7.2 Composition The CMDh is composed of one representative per Member State (plus Norway, Iceland, and Liechtenstein), appointed for a renewable period of 3 years. Member States may also appoint an alternate member, and observers from the EC and EU accession countries also participate in meetings. Information on the members and

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alternates of the CMDh is available on the CMDh website. The EMA provides the secretariat to the CMDh. 2.7.3 Meetings and reports The CMDh holds monthly meetings at the EMA lasting 3 days. After each meeting, the CMDh publishes a meeting report in the form of a press release. The CMDh press releases are available on the CMDh website. 2.7.4 Safety referrals The CMDh positions adopted in the context of safety-related referral procedures are currently published on the EMA website. Once a CMDh position is adopted, the EMA also publishes a press release summarizing the CMDh position. The CMDh website contains further information on the CMDh and its work, including statistics, guidance documents, question-and-answer documents, work plans, annual reports, and information on the applications referred to the CMDh. Similar description, composition, and responsibilities lie with the Coordination Group for Mutual Recognition and Decentralised ProceduresdVeterinary [14].

3. Legal framework for licensing medicines for human use in the EU 3.1 Introduction The EU legal framework guarantees high standards of quality and safety of medicinal products, while promoting the good functioning of the internal market with measures that encourage innovation and competitiveness. It is mainly composed of Directives and Regulations published by the EC. In this section, description of the regulatory requirements and rules governing the marketing

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3. Marketing authorization and licensing of medicinal products in EU: Regulatory aspects

authorization of medicinal products for human use in the EU, the legal framework of the process of their licensing, procedures to be followed (depending on type of medicinal product to be licensed and marketing policy of the applicant), as well as other related topics are briefly explained. Readers who are interested in veterinary medicines are referred to the main website of the EMA for further details. While every effort has been made to maintain enough clarity on this very pronged and difficult to follow subject, dragging the reader into deeper details causing distraction from the main points covered in this section has been best avoided. However, for further details of any of the topics discussed, the interested reader can review the original publications referred to in this section. The following is a presentation of the most relevant legislations concerning authorization for marketing medicinal products in the EU.

3.2 Directive 2001/83/EC [15] Since its publication in 2001, the Directive (2001/83/EC) has gone through a number of amendments, the latest of which was on November 16, 2012. While the reader is strongly encouraged to familiarize him/herself with the Directive in general, and with the definitions given under Article 1 in particular, it is beyond the scope of this chapter to discuss the whole Directive in detail but to focus only on the main articles that are directly related to the licensing and marketing authorization of medicinal products in the EU. 3.2.1 Article 6 No medicinal product may be placed on the market of a Member State unless a marketing authorisation has been issued by the competent authorities of that Member State in accordance with this Directive.

Also, under Article 6(1a) it is stated that the MAH shall be responsible for marketing the medicinal product and the designation of a representative shall not relieve the MAH of his/her legal responsibility. It is paramount for the pharmaceutical companies to familiarize themselves with the requirements of licensing medicinal products in the EU and rules governing the process. 3.2.2 Article 8(3)(i) Meeting the requirements of Article 6 is set under this article whereby results of the following studies are to be submitted: • Pharmaceutical (physicochemical, biological, or microbiological) tests; • Preclinical (toxicological and pharmacological) tests; • Clinical trials. Also, under Article 8(3)(ia), submission of a detailed description of the pharmacovigilance and, where appropriate, of the riskmanagement system that the applicant will introduce is to be made. 3.2.3 Article 10.1 For generic medicines: the applicant shall not be required to provide the results of pre-clinical tests and of clinical trials if he can demonstrate that the medicinal product is a generic of a reference medicinal product which is or has been authorised under Article 6 for not less than eight years in a Member State or in the Community.

Under the same article, the generic product cannot be placed on the market until 10 years have elapsed from the initial authorization of the reference product. The exclusivity of 10 years granted to the reference product can be extended to a maximum of 11 years if, during the first 8 years of those 10 years, the MAH obtains an authorization for one more new therapeutic indication.

3. Legal framework for licensing medicines for human use in the EU

3.2.4 Article 10.3 In cases where the medicinal product: 1. Does not fall within the definition of a generic medicinal product as provided in Article 10(2), paragraph (b) of the Directive. 2. Or where the bioequivalence cannot be demonstrated through bioavailability studies; 3. Or in case of changes in the active substance(s), therapeutic indications, strength, pharmaceutical form or route of administration, vis a-vis the reference medicinal product; the results of the appropriate preclinical tests or clinical trials shall be provided. 3.2.5 Article 10a The applicant shall not be required to provide the results of pre-clinical tests or clinical trials if he can demonstrate that the active substances of the medicinal product have been in well-established medicinal use within the Community for at least ten years, with recognised efficacy and an acceptable level of safety in terms of the conditions set out in the Annex. In that event, the test and trial results shall be replaced by appropriate scientific literature.

3.2.6 Article 10b In the case of medicinal products containing active substances used in the composition of authorised medicinal products but not hitherto used in combination for therapeutic purposes, the results of new preclinical tests or new clinical trials relating to that combination shall be provided in accordance with Article 8(3)(i), but it shall not be necessary to provide scientific references relating to each individual active substance.

This article is about combination products of two actives or more with the requirements for preclinical tests and clinical trials. There is always confusion between the requirements of this article and Article 10a. In other words, having a combination of two actives used for more than 10 years in the Community would not justify their application under 10a but should under Article 10b. The reason

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behind this is that the combination has not been in use in the Community in accordance with the requirements of Article 10a and safety and efficacy of the new combination should be assured as per Article 8(3)(i). However, if the combination has already been used for more than 10 years for the proposed indication, Article 10a would apply. 3.2.7 Article 10c Following the granting of a marketing authorisation, the authorisation holder may allow use to be made of the pharmaceutical, preclinical and clinical documentation contained in the file on the medicinal product, with a view to examining subsequent applications relating to other medicinal products possessing the same qualitative and quantitative composition in terms of active substances and the same pharmaceutical form.

The meaning of this article is to allow the MAH to have more than one license of the same product issued either to the same company or to another company that holds a consent from the original MAH. This article is only applicable to reference products and not to generics.

3.3 Regulation (EC) No. 726/2004 [16] The purpose of this regulation is to lay down Community procedures for authorization and supervision of medicinal products for human and veterinary use. This has undergone many amendments since it was first published in 2004, the latest of which was on June 5, 2013. It provides insight into the main articles of Directive 2001/83/EC as amended. Reference to this regulation will be made during the discussions of the different procedures adopted in the EU, avoiding repetition while focusing on the main points of interest.

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3. Marketing authorization and licensing of medicinal products in EU: Regulatory aspects

3.4 EudraLex [17] This is a collection of rules and regulations governing the marketing authorization of medicinal products in the EU defined by Directive 2001/83/EU as amended. It consists of 10 volumes. Concerning medicinal products for human use, they are: • • • • • •

Volume Volume Volume Volume Volume Volume

1: Pharmaceutical Legislation 2: Notice to Applicants 3: Guidelines 4: Good Manufacturing Practices 9: Pharmacovigilance 10: Clinical Trials

Volume 1 covers the pharmaceutical legislations concerning the authorization of medicinal products for human and veterinary use in the EU to include published Directives and Regulations. It provides access to the list of all the legislations and their history. Interested readers can access this volume by logging into EudraLex website given under reference no.17. Volumes 5, 6, 7, and 8 as well as Volumes 4 and 9 concern veterinary medicinal products. Volume 3 is no longer covered in EudraLex and referral to the EMA website is made. Of direct interest, Volume 2 (Notice to Applicants) has been prepared in accordance with Article 6 of Regulation (EC) No. 726/2004 and Annex I of Directive 2001/83/EC on the Community Code relating to medicinal products for human use. It is intended to facilitate the interpretation and application of the Union pharmaceutical legislation and is composed of three subvolumes: • Volume 2A deals with the procedure for marketing authorization. • Volume 2B deals with the presentation and content of the dossier. • Volume 2C deals with regulatory guidelines. Each subvolume contains a number of chapters. Volume 2A is composed of six chapters:

• Chapter 1 Marketing Authorizationdupdated June 2018 • Chapter 2 Mutual Recognitiondupdated February 2007 • Chapter 3 Union Referral Proceduresdupdated December 2016 • Chapter 4 Centralised Procedureddeleted in July 2005 replaced by the website of the EMA • Chapter 5 Variation GuidelinesdMay 2013 • Chapter 6 Community Marketing Authorisationdupdated November 2005 For the purpose of this section, focus on Chapter 1 only will be made. It provides a summary of the subjects covered in other chapters, highlighting the main points and applications that are of interest. For further details of any of the material discussed, reference to the respective chapter of Volume 2A is made. To ensure smooth flow of the presentation, citing references will be avoided, which can be seen in the original publication.

3.5 Volume 2AdChapter 1 This provides the general principles of the Union pharmaceutical legislation. 3.5.1 Marketing authorization A medicinal product may only be placed on the market in the EEA when a marketing authorization has been issued: • By the competent authority of a Member State for its own territory (national authorization); • Or when an authorization has been granted for the entire Union (a Union authorization) in accordance with Regulation (EC) No. 726/ 2004. 3.5.2 National authorization The competent authorities of the Member States are responsible for granting marketing

3. Legal framework for licensing medicines for human use in the EU

authorizations for medicinal products that are placed on their markets. To obtain a national marketing authorization, an application must be submitted to the competent authority of the Member State. However, and in cases where national authorizations are requested for the same medicinal product in more than one Member State and the MAH has received a marketing authorization in a Member State, the applicant/MAH must submit an application in the Concerned Member States (abbreviated CMS) using the procedure of mutual recognition (abbreviated MRP). The Concerned Member States should then recognize the marketing authorization already granted by the Reference Member State (RMS) and authorize the marketing of the product on their national territory. If no marketing authorization has been granted in the Union, the applicant may make use of a decentralized procedure (abbreviated DCP) and submit an application in all the Member States where it intends to obtain a marketing authorization at the same time and choose one of them as RMS. Based on the assessment report prepared by the RMS and any comments made by the CMS, marketing authorization should be granted in accordance with the decision taken by the RMS and CMS in this decentralized procedure. The marketing authorization must contain the summary of product characteristics (SmPC) according to Article 11 of Directive 2001/83/EC and the labeling and the package leaflet according to Articles 54, 55, 59, and 63 of Directive 2001/83/EC as amended. 3.5.3 Union authorizations The Union will grant marketing authorizations for medicinal products: • Referred to in the Annex to Regulation (EC) No. 726/2004, which may only be authorized via the centralized procedure (mandatory scope);

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• Referred to in Article 3(2) of Regulation (EC) No. 726/2004, relating to products containing new active substances, products that constitute a significant therapeutic, scientific, or technical innovation, or products for which the granting of a Union authorization would be in the interest of patients or animal health at Union level; • The applicant has to request confirmation that the product is eligible for evaluation through the centralized procedure (optional scope) and the EMA will decide on the matter; • A generic medicinal product of a centrally authorized medicinal product if not using the option in Article 3(3) of Regulation (EC) No. 726/2004. To obtain a Union authorization, an application must be submitted to the EMA. More details are provided in the original publication (Section 3.1 of Chapter 1 of Notice to Applicants). Such a marketing authorization is valid throughout the Union and confers the same rights and obligations in each of the Member States as a marketing authorization granted by that Member State. Once a central marketing authorization has been issued, the maintenance of existing national marketing authorization or the issuing of new national marketing authorizations for the same medicinal product could be envisaged only as long as the therapeutic indications are different in national and central marketing authorizations. 3.5.4 Notion of “global marketing authorization” Based on Article 6(1) second subparagraph of Directive 2001/83/EC, the global marketing authorization contains the initial authorization and all variations and extensions thereof, as well as any additional strengths, pharmaceutical form, administration routes, or presentations authorized through separate procedures, including in different Member States within the

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EU, and under a different name, granted to the MAH of the initial authorization. Under this section, three different scenarios and notion of global marketing authorization are cited: 1. If the medicinal product being assessed contains a modification of an existing active substance, it should be clarified during the marketing authorization procedure whether the product contains a new active substance or not. If the assessment report does not indicate that the product contains a new active substance, it will be considered that the product at stake contains the same active substance and belongs to the global marketing authorization of the already authorized medicinal product(s) as described in Article 6(1) of Directive 2001/ 83/EC: Example: Active substance A in MP1 / Active substance A0 in MP2. 2. If the medicinal product being assessed contains within the same pharmaceutical form a combination of active substances, it will form a new and unique medicinal product requiring a separate marketing authorization, regardless of whether all of the active substances contained therein were already authorized in a medicinal product or not. The applicant must demonstrate that each active substance has a documented therapeutic contribution within the combination and therefore all compounds are different active substances. The authorization for this new combination medicinal product is not considered to fall within the scope of the global marketing authorizations of the already authorized medicinal product(s) as described in Article 6(1) of Directive 2001/83/EC. Examples: Active substance A in MP1, Active substance B in MP2 / Active substances AþB in MP3.

Active substances AþB in MP1, Active substances CþD in MP2 / Active substances AþC in MP3. Active substances AþB in MP1, Active substance C in MP2 / Active substances AþC in MP3. Active substances AþB in MP1 / Active substance AþC in MP2. 3. If the medicinal product being assessed contains only one active substance, which was part of an authorized combination product, the new medicinal product will form a new and unique medicinal product requiring a separate marketing authorization. The authorization for the new medicinal product is not considered to fall within the scope of the global marketing authorizations of the already authorized combination medicinal product as described in Article 6(1) of Directive 2001/ 83/EC. Multiple applications of the same MAH are covered by the notion of “global marketing authorization.” 3.5.5 Validity of the marketing authorization 3.5.5.1 Renewal

Marketing authorizations granted in the Union have an initial duration of 5 years. After these 5 years, the marketing authorization may be renewed on the basis of a reevaluation of the riskebenefit balance. To this end, the MAH must provide the EMA or the national competent authority with a consolidated version of the file in respect of quality, safety, and efficacy, including all variations introduced since the marketing authorization was granted, at least 9 months before the marketing authorization ceases to be valid. Once renewed, the marketing authorization is valid for an unlimited period unless the Commission or the national competent authority decides, on justified grounds relating to pharmacovigilance, to proceed with one additional 5-year renewal.

3. Legal framework for licensing medicines for human use in the EU

Recommendations regarding the content of the consolidated file for the renewal are provided in the EMA Guideline on the Processing of Renewals in the Centralised Procedure [18] and CMDh Best Practice Guide on the Processing of Renewals in the Mutual Recognition Procedure/Decentralized Procedure [19]. 3.5.5.2 Cessation of the marketing authorization if the medicinal product is not marketed

Any authorization that within 3 years of its granting is not followed by the actual placing on the market of the authorized product in the authorizing Member State or on the Union market will cease to be valid. Also, when an authorized product previously placed on the market in the authorizing Member State or in the Union is no longer actually present on the market for a period of 3 consecutive years, the authorization for that product will cease to be valid. A medicinal product is “placed on the market” at the date of release into the distribution chain. It is the date when the product comes out of the control of the MAH. For centrally authorized medicinal products, “placed on the Union market” means that the medicinal product is at least marketed in one Member State of the Union. For nationally authorized products “placed on the market in the authorizing Member State” means that the medicinal product is on the market of the Member State that has granted the marketing authorization. This is independent of the authorization procedure used (decentralized, mutual recognition, or purely national procedure). After a marketing authorization has been granted, the holder of the authorization must inform the competent authority of the authorizing Member State or the EMA of the date of actual marketing of the medicinal product in that Member State or in the Union, considering the various presentations authorized. The holder must also notify the national competent authority or the EMA if the product

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ceases to be placed on the market, either temporarily or permanently. 3.5.6 Naming of a medicinal product The marketing authorization must contain the name of the medicinal product, which may be either an invented name, or a common or scientific name (when available, the international nonproprietary name of the active substance(s)) accompanied by a trade mark or the name of the MAH. In the case of Union authorizations granted following applications through the centralized procedure, it is important that applicants identify at an early stage a name that would be valid throughout the Union when using the centralized procedure. For applications through the mutual recognition and decentralized procedures, it is recommended whenever feasible that the same name for a given medicinal product should be used in all Member States. If a different name is to be used, it should be quoted in a covering letter from the applicant to the relevant competent authorities. Where a generic of a medicinal product authorized through the centralized procedure is authorized by the competent authorities of the Member States, the generic medicinal product has to be authorized under the same name in all the Member States where the application has been made. For these purposes, all the linguistic versions of the international nonproprietary name are considered to be the same name (Article 3(3) of Regulation (EC) No. 726/ 2004). 3.5.7 Transparency In accordance with Article 21 of Directive 2001/83/EC, the national competent authorities are obliged to make publicly available the decision granting the marketing authorization. This decision is appended with the package leaflet, the SmPC, and any possible condition to the marketing authorization.

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3.5.8 Multiple application 3.5.8.1 Centralized application

In the framework of the centralized procedure only one marketing authorization may be granted to an applicant for a specific medicinal product. However, according to Article 82(1) second subparagraph of Regulation (EC) 726/2004 the same applicant can submit more than one application for the same medicinal product when there are objective verifiable reasons: • Relating to public health regarding the availability of medicinal products to healthcare professionals and/or patients or • For comarketing reasons. In such case, the Commission will inform the applicant whether the conditions are met before he submits his application to the EMA. 3.5.8.2 Mutual recognition and decentralized procedures

There are no corresponding provisions in Directive 2001/83/EC that apply to these procedures. However, to avoid submission of multiple applications in different Member States and handled outside, the principles of mutual recognition laid down in Chapter IV of Directive 2001/83/EC should be observed: • Reference to any authorization obtained for that medicinal product should be provided with the application for a marketing authorization; as far as possible, the same RMS should be used in the case of multiple applications; • Article 18 should be relied on to avoid multiple applications that are used to obtain marketing authorizations for the same medicinal product in different Member States outside the procedural framework of Chapter IV of Directive 2001/83/EC; • The applicant may decide whether the mutual recognition procedure or the decentralized procedure is used for obtaining the multiple marketing authorizations.

See CMDh Recommendations on Multiple Applications in Mutual Recognition and Decentralised Procedures (June 2007) [20]. 3.5.8.3 Concept of “applicant and marketing authorization holder”

An “applicant” and “marketing authorization holder” can be a physical or legal entity. However, for the purposes of the application of the pharmaceutical rules, it is noted that: • Applicants and MAHs belonging to the same company group or that are controlled by the same physical or legal entity are to be considered as one entity. • Applicants and MAHs that do not belong to the same company group and are not controlled by the same physical or legal entity are to be considered as one applicant/MAH: • If they have concluded tacit or explicit agreements concerning the marketing of the same medicinal product for the purposes of the application of the pharmaceutical rules regarding that medicinal product. • This includes cases of joint marketing but also cases where one party licenses to the other party the right to market the same medicinal product in exchange for fees or other considerations. From above, it is inferred the applicant and the marketing authorization holder are not necessarily of the same entity and could be of different companies. However as per the EU requirements both should have a proof of establishment in EEA and for this reason, most of the non-EU companies would have a representing office in EU.

3.6 Marketing authorization procedures In addition to independent national procedure, in the EU there are three different procedures, namely: 1. Centralized procedure 2. Decentralized procedure 3. Mutual recognition procedure

3. Legal framework for licensing medicines for human use in the EU

3.6.1 Centralized procedure In this procedure there are two possibilities: 1. Medicinal products that fall within the mandatory scope of the centralized procedure in accordance with the Annex to Regulation (EC) No. 726/2004, the application is submitted to the EMA. 2. Medicinal products that fall within the optional scope of the centralized procedure in accordance with Article 3(2) and 3(3) of Regulation (EC) No. 726/2004 where the applicant wishes to obtain a Union marketing authorization. Following the scientific evaluation and upon receipt of the opinion, the EC drafts a decision on a Union marketing authorization and, after consulting the Standing Committee for Medicinal Products for Human Use, grants a marketing authorization. 3.6.2 Decentralized procedure and mutual recognition procedure Both procedures are based on the recognition by national competent authority’s assessment performed by the authorities of oneMember State. According to the European Court of Justice, [.] Article 28 of Directive 2001/83/EC [.] confers a Member State in receipt of an application for mutual recognition only a very limited discretion in relation to the reasons for which that Member State is entitled to refuse to recognise the marketing authorisation in question. In particular, as regards any assessment going beyond the verification of the validity of the application with regard to the conditions laid down in Article 28, the Member State concerned, except where there is a risk to public health, must rely on the assessments and scientific evaluations carried out by the reference Member State. Although the facts of the case relate to a MRP, the ECJ is interpreting Article 28 (4) which applies both to MRP and DCP.

3.6.3 Decentralized procedure For medicinal products not falling within the mandatory scope of the centralized procedure,

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the applicant may request one or more concerned Member State(s) to approve a draft assessment report, SmPC, and labeling and package leaflet as proposed by the chosen RMS. An application is submitted to the competent authorities of the RMS and the concerned Member State(s), together with the information and particulars referred to in Articles 8, 10, 10a, 10b, 10c, and 11 of Directive 2001/83/EC. At the end of the decentralized procedure with a positive agreement, a national marketing authorization will be issued in the RMS and the concerned Member State. 3.6.4 Mutual recognition procedure This procedure is based on the mutual recognition by concerned Member State(s) of a national marketing authorization granted by the RMS. At the end of the mutual recognition procedure, a national marketing authorization will be issued in the concerned Member State(s). 3.6.5 Independent national procedures These procedures will apply to medicinal products that are not to be authorized in more than one Member State.

3.7 Paediatric requirements for medicinal products Regulation (EC) No. 1901/200620 of the European Parliament and of the Council on Medicinal Products for Paediatric Use entered into force on January 26, 2007. It aims to facilitate the development and availability of medicinal products for use in the paediatric population. To attain this goal, the regulation places on applicants certain obligations, the main one being submission of data on the use of a medicinal product in children obtained in accordance with an agreed PIP by the EMA. Provided that the requirements of Regulation 1901/2006 are fulfilled, the applicants may then be eligible for a reward, as provided in Title V of this Regulation,

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that may be an extension of the supplementary protection certificate, extension of market exclusivity, or data/market protection, as the case may be. Information on guidelines developed by the CMDh are given on the website [21].

3.8 Union referrals In certain circumstances in the framework of marketing authorizations granted by the competent authorities of the Member States, a Union procedure, involving a scientific opinion by, as appropriate, the CHMP/PRAC, can be triggered. This procedure is commonly called Union “referral,” which may be triggered in the cases listed in the following. 3.8.1 Referral according to Article 29 of Directive 2001/83/EC Where one or more concerned Member States cannot agree on the recognition of an authorization already granted in a mutual recognition procedure or a final assessment and product information prepared by the RMS in view of granting the marketing authorization in a decentralized procedure due to a potential serious risk to public health. The points of disagreement must be referred to the coordination group provided by Article 27 of that Directive. Where the Member States concerned by the procedure fail to reach an agreement within the coordination group, the matter is referred to the CHMP for application of the procedure laid down in Articles 32e34 of Directive 2001/83/EC. This referral is automatic in the sense that, once a Member State has raised a concern on the grounds of potential serious risk to public health within the meaning of Article 29(1), withdrawal of the marketing authorization application in that Member State does not prevent the concern from being analyzed within the coordination group and, in the absence of an agreement therein, the EMA. The expression “potential serious risk to public health” is defined in the Commission’s

Guideline on the definition of a potential serious risk to public health in the context of Article 29(1) and (2) of Directive 2001/83/EC [22]. 3.8.2 Referral in accordance with Article 30(1) of Directive 2001/83/EC If two or more applications submitted in accordance with Articles 8, 10, 10a, 10b, 10c, and 11 of that Directive have been made for marketing authorization for a particular medicinal product, and if Member States have adopted divergent decisions concerning the authorization of the medicinal product or its suspension or revocation, a Member State, the Commission, applicant, or the MAH may refer the matter to the CHMP. 3.8.3 Referral in accordance with Article 30(2) of Directive 2001/83/EC To promote harmonization of authorizations for medicinal products authorized in the Union, Member States must, each year, forward to the coordination group a list of medicinal products for which a harmonized SmPC should be drawn up. The coordination group must lay down a list considering the proposals from all Member States and will forward this list to the Commission. The Commission or a Member State, in agreement with the Agency and considering the views of interested parties, may refer these products to the committee. 3.8.4 Referral in accordance with Article 31 of Directive 2001/83/EC The Member States or the Commission or the applicant or the MAH must, in specific cases where the interests of the Union are involved, refer the matter to the committee for the application of the procedure laid down in Articles 32, 33, and 34 before any decision is reached on a request for a marketing authorization or on the suspension or revocation of an authorization, or any other variation to the terms of a marketing authorization that appears necessary. Where the referral results from the evaluation of data relating to pharmacovigilance the matter must be referred to the PRAC. Its final

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recommendation will be forwarded to the CHMP or the coordination group, as appropriate. However, when one of the criteria listed in Article 107i(1) is met, the procedure laid down in Articles 107ie107k must apply. Where the referral concerns a range of medicinal products or a therapeutic class, the Agency may limit the procedure to specific parts of the authorization. In such a case, Article 35 must apply to those medicinal products only if they were covered by the authorization procedures referred to in this chapter (decentralized and mutual recognition procedures). 3.8.5 Referral in accordance with Article 107i of directive 2001/83/EC A Member State or the Commission, as appropriate, must, on the basis of concerns resulting from the evaluation of data from pharmacovigilance activities: (a) Initiate the procedure provided for in the section by informing the other Member States, the Agency, and the Commission where it considers suspending or revoking a marketing authorization, prohibiting the supply of a medicinal product, refusing the renewal of a marketing authorization, or it is informed that the MAH, on the basis of safety concerns, has interrupted the placing on the market of a medicinal product or has taken action to have a marketing authorization withdrawn, or intends to take such action or has not applied for the renewal of a marketing authorization. (b) Inform the other Member States, the Agency, and the Commission where it considers that a new contraindication, a reduction in the recommended dose or a restriction to the indications of a medicinal product is necessary. The information must outline the action considered and the reasons therefor. (c) Initiate the procedure in any of the cases referred in the paragraph (b), when urgent action is considered necessary.

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3.9 Application types The legal requirements and the procedures for making an application for a marketing authorization in European Union are set out in Directive 2001/83/EC and in regulation (EC) No. 726/ 2004, which are briefly highlighted in the early part of this Chapter. A brief description of these legal requirements and procedures is set out in this chapter for applications according to: • Article 8(3) of Directive 2001/83/EC • Article 10 of Directive 2001/83/EC, relates to generic medicinal products, “hybrid” medicinal products, and similar biological medicinal products; • Article 10a of Directive 2001/83/EC, relates to applications relying on well-established medicinal use supported by bibliographic literature; • Article 10b of Directive 2001/83/EC, relates to applications for new fixed combinations of active substances in a medicinal product; • Article 10c of Directive 2001/83/EC, relates to informed consent from an MAH for an authorized medicinal product. 3.9.1 Applications according to Article 8(3) of Directive 2001/83/EC An application for marketing authorization must be accompanied by the particulars and documents set out in Article 8(3) of Directive 2001/83/EC and therefore the following documentation must be included in the dossier: • Pharmaceutical (physicochemical, biological, or microbiological) tests; • Preclinical (toxicological and pharmacological) tests; • Clinical trials. For such applications, the relevant published literature also has to be submitted and these scientific publications can be used as supportive data.

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Types and details of the studies included in each of the three tests are detailed in Volume 2B of the Notice to Applicants [23]. It provides guidance to the compilation of the dossiers for application for EU marketing authorization applicable for the centralized and national procedures, including mutual recognition and decentralized procedures. Further details about these procedures are explained in this section. Volume 2B of Notice to Applicants takes account of the international agreement on the structure and format of the common technical document (CTD), which were agreed in November 2000 within the International Conference on Harmonisation (ICH) framework and further documents and guidelines agreed upon since that time. More details about ICH and guidelines are given on the ICH website [24]. For a quick view of the content of the CTD, a schematic pyramid used by the ICH and EU websites is presented in Fig. 3.3. It is beyond the scope of this section to discuss the details and content of the dossier but it can be

seen under Volume 2B of the Notice to Applicants mentioned earlier. Of special interest, within module 5 of the CTD, and for clinical trials carried outside the EU, a statement to that effect confirming the compliance to the ethical requirements of Directive 2001/20/EC should be submitted. Furthermore, in the “Guideline on the Investigation of Bioequivalence, 2010” [25], bioequivalence trials conducted in the EU/EEA have to be carried out in accordance with Directive 2001/20/EC. Trials conducted outside the Union and intended for use in a marketing authorization application in the EU/EEA have to be conducted to the standards set out in Annex I of the Community Code, Directive 2001/83/EC as amended. 3.9.2 Applications according to Article 10 of Directive 2001/83/EC 3.9.2.1 Reference medicinal product

Reference can be made to the dossier of a reference medicinal product for which a marketing authorization has been granted in the Union

FIGURE 3.3 The common technical document (CTD) triangle. Module 1 is region specific and modules 2, 3, 4, and 5 are intended to be common for all regions.

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in accordance with Articles 8(3), 10a, 10b, or 10c of Directive 2001/83/EC. The application form in module 1 of the dossier for an Article 10 application should clearly identify the reference product in order for the RMS, in case of mutual recognition procedure/decentralized procedure, to prepare the assessment report. Each product within the global marketing authorization may be chosen as the reference medicinal product. Reference cannot be made to the dossier of a medicinal product for which a marketing authorization has been granted in the Union in accordance with Article 10(1). Data supporting applications approved under Article 10(3) (e.g., new indications, strength, route of administration, pharmaceutical form) do not benefit from periods of exclusivity. As an exception, when specifically provided for new therapeutic indications based on Article 10(5). For example, Product B (Company 2) was approved according to Article 10(3) based on additional preclinical and/or clinical studies (e.g., supporting a new indication, strength, pharmaceutical form, or route of administration) to those submitted in support of the reference product (Product A, Company 1). A subsequent application may be submitted for Product C (Company 3), which refers to data supporting the reference product (Product A) and also to the data submitted in support of Product B (approved according to Article 10(3)), provided that any data exclusivity awarded in respect of a possible new therapeutic indication for Product B has elapsed. The application for Product C may be accepted irrespective of whether Products A and B belong to the same global marketing authorization. In such a case, Product A would be the reference medicinal product in support of the application for Product C. Applicants proposing such a marketing authorization application are advised to contact the competent authorities in advance of the submission.

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Reference must be made to a product that is or has been authorized in the Union (i.e., a marketing authorization has been granted for the reference medicinal product, but it may have ceased to exist). In case, the reference medicinal product is no longer produced and placed in the Union market; demonstration of the bioequivalence with the reference medicinal product through bioavailability studies should, however, be performed on batches that have been authorized within the Union. Authorizations for generic medicinal products are linked to the “original” authorization. This does not, however, mean that withdrawal of the authorization for the reference product leads to withdrawal of the authorization for the generic product. An application according to Article 10 of Directive 2001/83/EC cannot be filed simultaneously with an application for a reference product. The MAH of the reference medicinal product can file an application on the basis of Article 10 to his/her own medicinal product, provided that the requirements of Article 10 are fulfilled, for example, the data exclusivity period has expired. 3.9.2.2 European reference medicinal product

According to Article 10(1) third subparagraph of Directive 2001/83/EC, a generic application can also be submitted in a Member State although the reference medicinal product has never been authorized in that Member State. In that case, a reference medicinal product in another Member State should be identified, a so-called European reference medicinal product. In these cases, the applicant has to identify in the application form the name of the Member State in which the reference medicinal product is or has been authorized. It is also a prerequisite that the period of data exclusivity has expired in the Member State of the reference medicinal product.

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At the request of the competent authority of the Member State in which the application is submitted, the competent authority of the other Member State should transmit, within a period of 1 month, a confirmation that the reference medicinal product is or has been authorized together with the full composition of the reference product and if necessary other relevant documentation.

to be the same pharmaceutical form for the purposes of Article 10: • and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies. Bioavailability studies need not be required if the applicant can demonstrate that the generic medicinal product meets the relevant criteria as defined in the detailed guideline on the investigation of bioequivalence.

3.9.2.3 Particularities for application according to Article 10

Where bioequivalence cannot be demonstrated through bioavailability studies, Article 10(3) requires that the results of appropriate preclinical tests or clinical trials will be provided.

Article 10 constitutes a single legal base for the submission of applications. The content of such applications must comply with the requirements set out therein. Directive 2001/83/EC defines a generic medicinal product in Article 10(2)(b) as a medicinal product that has: • The same qualitative and quantitative composition in active substances as the reference medicinal product. This requirement extends only to the active substance(s) and not to the other ingredients of the product. However, differences in excipient composition or differences in impurities must not lead to significant differences as regards safety and efficacy: The different salts, esters, ethers, isomers, mixtures of isomers, complexes, or derivatives of an active substance must be considered to be the same active substance, unless they differ significantly in properties with regard to safety and/or efficacy. • The same pharmaceutical form as the reference medicinal product, A generic product and a reference product may be considered to have the same pharmaceutical form if they have the same form of administration as defined by the Pharmacopoeia. Furthermore, the various immediate release oral forms, which would include tablets, capsules, oral solutions, and suspensions, are considered

3.9.2.4 Applications in accordance with paragraph 3 of Article 10 (“hybrid medicinal product”)

In certain circumstances in the framework of an application under Article 10, the results of the appropriate preclinical tests or clinical trials shall be provided. These applications will thus rely in part on the results of preclinical tests and clinical trials for a reference product and in part on new data. The extent of the additional studies required in the framework of an Article 10(3) application depends on the changes introduced vis-a-vis the reference medicinal product (e.g., new strength, new route of administration, new therapeutic indication) and will be a matter of scientific assessment by the relevant competent authority. Article 10(3) considers three circumstances where such additional data will be necessary: • Where the strict definition of a “generic medicinal product” is not met. Some examples and requirements are given under Section 3.12 at the end of the chapter. • Where bioavailability studies cannot be used to demonstrate bioequivalence (for example, where the new product is for locally applied/locally acting medicinal products). Therapeutic equivalence (safety/efficacy) of the generic product compared to the

3. Legal framework for licensing medicines for human use in the EU

reference product should be demonstrated (cf. guideline). • Where there are changes in the active substance(s), therapeutic indications, strength (outside the current approved range), pharmaceutical form, or route of admini-stration of the generic product compared to the reference product, clinical/bioavailability studies would be required. 3.9.2.5 Applications according to Article 10a of Directive 2001/83/EC

According to this article, it is possible to replace results of the preclinical and clinical trials with detailed references to published scientific literature if it can be demonstrated that the active substances of a medicinal product in the claimed therapeutic indication have been in wellestablished medicinal use within the Union for at least 10 years, with recognized efficacy and an acceptable level of safety. The adequacy of the bibliographic evidence has to be assessed on a case-by-case basis in the understanding that applications under Article 10a do not lower the requirements of safety and efficacy that must be met. 3.9.2.6 Well-established medicinal use

Annex I of Directive 2001/83/EC lays down specific rules for the demonstration of a wellestablished medicinal use, with recognized efficacy and an acceptable level of safety. The following criteria should be considered: • The time over which a substance has been used with regular application in patients; quantitative aspects of the use of the substance, considering the extent to which the substance has been used in practice, the extent of use on a geographical basis, and the extent to which the use of the substance has been monitored by pharmacovigilance or other methods; • The degree of scientific interest in the use of the substance (reflected in the published

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scientific literature) and the coherence of scientific assessments. The period of time required for establishing a well-established medicinal use of a constituent of a medicinal product must not be less than one decade from the first systematic and documented use of that substance as a medicinal product in the Union. Well-established use refers to the use for a specific therapeutic use. If well-known substances are used for entirely new therapeutic indications and it is not possible to solely refer to a well-established use, then additional data on the new therapeutic indication together with appropriate preclinical and human safety and/or efficacy data should be provided. In such a case, another legal basis should be used for the marketing authorization application. Marketing authorization applications for fixed combinations intended to be used in patients who are already stabilized on optimal doses of the combination of the same, but separately administered active substances, taken at the same dose interval and time, can be submitted on the basis of Article 10a. In such cases, the detailed references to published scientific literature submitted must concern the systematic and documented use of the active substances in combination. It is nevertheless possible to include information on the individual active substances in the application. This will typically occur where the applicant intends to justify the absence of certain specific data on the combination by reference to the information available on the individual substances. A product approved under Article 10a can act as a Reference Medicinal Product for a subsequent Article 10 application as they have been approved under a full dossier and data exclusivity/market protection periods of 10 years would apply. From a legal perspective, a generic to a reference medicinal product which had been licensed under Article 8(3)(ia) can also claim well established use (WEU) once the 10 years of

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exclusivity elapsed. The difference is that in 10.1 application reference to a reference medicinal product should be made supported by bioequivalence study or its absence should be justified under the biowaiver regulation. However, in 10a application reference to a reference medicine (approved for more than 10 years) would not be required and efficacy and safety of the product can be claimed through scientific literature survey and citation. Because of this possibility, to the acceptance of the competent authority, the claim for WEU should be well justified. 3.9.2.7 Documentation

The applicant should provide a detailed description of the strategy used for the search of published literature and the justification for inclusion of references in the application. The reference must be made to “published scientific literature.” The term “published” literature implies that the text must be freely available in the public domain and published by a reputable source, preferably peer reviewed. All documentation, both favorable and unfavorable, should be communicated. If documentation is lacking, a justification should be given. If parts of the dossier are incomplete, particular attention must be paid to explain why in the overall overview/summaries. When compiling published scientific literature, applicants should also include postmarketing experience with medicinal products containing the same active substance. Copies of the full text of the literature, including necessary translations, must be submitted. 3.9.2.8 Applications according to Article 10b of Directive 2001/83/EEC

The combination of active substances within a single pharmaceutical form of administration according to this provision is a so-called “fixed combination.” A key principle of the acquis is that there must be a marketing authorization for each medicinal

product that is put on the EU market. Therefore the fixed combination definition is limited to active substances contained in a same pharmaceutical form of administration, the so-called “fixed combination.” The combination of active substances, where active substances are included in separate pharmaceutical forms and presented in a combination pack, cannot be considered as fixed combination. In the case of an application on the basis of Article 10b of Directive 2001/83/EC, the applicant does not have to provide scientific references relating to each individual active substance. Applications for fixed combination medicinal products under Article 10b are conditioned to the fact that the individual substances have been the object of a marketing authorization in the EEA via a Union or national procedure, even though it is not in the same Member State. In case the dossier is only composed of references to published scientific literature, the legal basis would not be Article 10b of Directive 2001/83/EC, but possibly 10a if all requirements are fulfilled. 3.9.2.9 Applications according to Article 10c of Directive 2001/83 /EC

A derogation from the requirements to submit all of the information required in Article 8(3)(i) is provided by Article 10c of Directive 2001/83/EC for so-called “informed consent” marketing authorization applications. Despite the fact that the provision contains criteria that are common to the definition of a generic medicinal product in Article 10, Article 10c does not concern generic medicinal products. An informed consent application does not have to cover all presentations/indications of the medicinal product with regard to which consent is given. Consent may be given to use the documentation contained in the file of the relevant medicinal product for a given presentation/indication provided that the application

3. Legal framework for licensing medicines for human use in the EU

relies on that consent as regards all three modules of the dossier. It is a prerequisite for the use of Article 10c that consent has been obtained for all three modules containing the pharmaceutical, preclinical, and clinical data. It is not possible to use Article 10c as a legal basis for an application consisting of the applicant’s own module 3 and for which consent has been given for modules 4 and 5. In such cases the legal basis for the application is Article 8(3). An informed consent application cannot cover more presentations or indications than the medicinal product with regard to which consent is given. The concept of “European reference medicinal product” is laid down by Article 10 and is applicable in case of application in accordance with Article 10. It does not apply in the context of applications under Article 10c. In addition, it should be noted that an informed consent application is only possible if there is still a valid marketing authorization to which consent is given. Furthermore, informed consent applications need to respect the following: • For a central marketing authorization, the informed consent application has to follow the centralized procedure; • For a national marketing authorization, the informed consent application has to follow a national procedure (either pure national or mutual recognition procedure or decentralized procedure). A prerequisite is that the marketing authorization is granted in this/these Member State(s). It follows that an application under Article 10c can only be submitted to a Member State where the medicinal product with regard to which consent is given is authorized. The applicant must show proof that the MAH of the reference product has consented that the dossier of that product is used for the purpose of examining the application in question.

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The “informed consent” product applicant must have permanent access to the documentation to fully carry out his responsibilities. For the information contained in the Active Substance Master File a new letter of access in connection with the informed consent application should be included, without prejudice to the restrictions on access to the Manufacturer Restricted Part of the Active Substance Master File. Nevertheless, in UK only and not in any other EU member state, it is permissible to duplicate the license of a generic medicinal product conditional to be issued to another company not linked to the MAH.

3.10 Data exclusivity and market protection This subject is more legal than technical, and the reader is recommended to seek legal advice on this subject prior to submission to ensure compliance. However, in this chapter a very short description of the main points that are of relevance to the regulatory affair and dossier submission is briefly made: The medicinal product, once authorized on the basis of Article 10, can, however, only be placed on the market 10 or 11 years after the authorization of the reference medicinal product, depending on the protection period applicable for the reference medicinal product. The protection period in the concerned Member State must also be taken into consideration before placing the medicinal product on its market. For products authorized by the national competent authorities, according to the first subparagraph of Article 10(1) of Directive 2001/83/ EC as amended by Directive 2004/27/EC, the applicant is not required to provide the results of preclinical tests and of clinical trials if he can demonstrate that the medicinal product is a generic of a reference medicinal product that is or has been authorized under Article 6 for not less than 8 years in a Member State or in the Union.

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According to the second subparagraph of Article 10(1), generic products authorized in this way must not be placed on the market until 10 years have elapsed from the initial authorization of the reference product. The period of 8 years from initial authorization of the reference product provides a period of so-called “data exclusivity,” after which valid applications for generic products can be submitted and lead to the granting of a marketing authorization. The period of 10 years from initial authorization of the reference product provides a period of so-called “market protection” after which generic products authorized in this way can be placed on the market. The same periods of protection apply in the case of centrally authorized products pursuant to Article 14(11) of Regulation (EC) No. 726/ 2004. 3.10.1 Protection periods and global marketing authorization For the notion of global marketing authorization, see Section 2.3. Global marketing authorization contains the initial authorization and all variations and extensions thereof, as well as any additional strengths, pharmaceutical form, administration routes, or presentations authorized through separate procedures and under a different name, granted to the MAH of the initial authorization. In accordance with Article 6(1) of Directive 2001/83/EC, all these presentations of a given product are considered to be part of the same marketing authorization for the purposes of applying the rules on data exclusivity and marketing protection. This means that for a reference medicinal product, the start of the data exclusivity and market protection periods is the date when the first marketing authorization was granted in the Union in accordance with the pharmaceutical acquis. New additional strengths, pharmaceutical form, administration routes, presentations, as well as any variation and extensions do not restart or prolong this period. All additional strengths, pharmaceutical

form, administration routes, presentations, as well as any variation and extensions have the same end point of the data exclusivity and market protection periods, namely 8 and 10 years after the first marketing authorization was granted, respectively. This will apply even if the new presentation has been authorized to the same MAH through a separate procedure, national or centralized procedure, irrespective of the legal basis and under a different name. This 10-year period can only be prolonged in the case of certain new indications. 3.10.1.1 Extension of the 10-year period in Article 10(1) in the case of new therapeutic indications

In accordance with the fourth subparagraph of Article 10(1) of Directive 2001/83/EC, the 10-year period of marketing protection may be extended by 1 year in the event of authorization of new therapeutic indications representing a significant clinical benefit in comparison with existing therapies. The additional year of marketing protection applies to the global marketing authorization for the reference medicinal product. Generic products, with or without the new therapeutic indication, may not be placed on the market until expiry of the 11th year. To benefit from the additional year, the new indication must be approved during the first 8 years since the initial marketing authorization has been granted. The overall period of protection cannot exceed 11 years. Therefore this provision can be used only once per “global marketing authorization” within the meaning of Article 6(1) of Directive 2001/83/EC. Guidance on elements required to support the significant benefit in comparison with existing therapies of a new therapeutic indication to benefit from an extended (11 years) marketing protection period is available [26]. 3.10.1.2 One-year period of protection for new indications of well-established substances

Article 10(5) of Directive 2001/83/EC reads: “In addition to the provisions laid down in

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paragraph 1, where an application is made for a new indication for a well-established substance, a non-cumulative period of one year of data exclusivity will be granted, provided that significant pre-clinical or clinical studies were carried out in relation to the new indication.” An applicant referring to Article 10(5) must provide justification regarding the existence of a new indication, of a well-established substance, and of significant preclinical or clinical studies. The new indication can be included either in the existing marketing authorization via a Type II variation or submitted with an application for a new marketing authorization. The data exclusivity period is noncumulative to other periods of protection: it refers exclusively to the data concerning the new indications. Therefore the concerned medicinal product could be used as reference medicinal product with the exclusion of the indication(s), which is covered by this data exclusivity if the medicinal product fulfills the general requirements of reference medicinal product. Such data exclusivity period is an incentive for development of new indications, while data protection would not otherwise apply. Guidance on a new therapeutic indication for a well-established substance is available [27]. 3.10.1.3 One-year period of protection for data supporting a change of classification

Article 74a of Directive 2001/83/EC reads: “Where a change of classification of a medicinal product has been authorised on the basis of significant pre-clinical tests or clinical trials, the competent authority shall not refer to the results of those tests or trials when examining an application by another applicant for or holder of marketing authorisation for a change of classification of the same substance for one year after the initial change was authorised.” For further guidance please refer to the Guideline on Changing the Classification for the Supply of a Medicinal Product for Human Use, available at [28].

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3.11 Variations and extensions 3.11.1 Variations Throughout the life of a medicinal product, the MAH is responsible for the product that is placed on the market. The MAH is required to consider technical and scientific progress, and to make any amendments/variations that may be required to ensure quality and compliance with the current requirements. Such variations may involve changes to the product information or changes to the technical dossier initially submitted. The procedures for the approval of variations have been set out in Commission Regulation (EC) No. 1234/2008 [29] concerning the examination of variations to the terms of marketing authorizations for medicinal products for human use and veterinary medicinal products. It has been amended by Regulation (EU) 712/2012) [30]. In accordance with Article 4(1) of the Variations Regulation, guidelines on the details of the various categories of variations, on the operation procedures laid down in Chapters II, IIa, III, and IV of that Regulation, as well as on the documentation to be submitted pursuant to these procedures were drawn by the EC. These guidelines are intended to facilitate the interpretation and application of the Variations Regulation. They provide details on the application of the relevant procedures, including a description of all the relevant steps from the submission of an application for a variation to the final outcome of the procedure on the application. The following categories of variations, defined in Article 2 of the Variations Regulation, are defined: • • • • •

Minor variations of Type IA Minor variations of Type IB Major variations of Type II Extensions Urgent safety restriction

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Only the EC and the EMA, respectively, are responsible for any variations relating to centrally authorized products. In the case of medicinal products for human use, the introduction of changes to the labeling or package leaflet that is not connected with the SmPC is not governed by the procedures of the Variations Regulation. In accordance with Article 61(3) of Directive 2001/83/EC, these changes are to be notified to the relevant competent authorities and they may be implemented if the competent authority has not objected within 90 days. It must be noticed that where a group of variations consists of different types of variations, the group must be submitted and will be handled according to the “highest” variation type included in the group. For instance, a group consisting of an extension and a major variation of Type II will be handled as an extension application; a group consisting of minor variations of Type IB and Type IA will be handled as a Type IB notification. The application form for variations to a marketing authorization for medicinal products (human and veterinary) is available online [31]. The conditions and requirements for submission for each of these categorized variations are very different, so are the timetable and procedures governing the assessment and notification of the outcome. Providing details is avoided and the following is a brief description of the type of variations. 3.11.1.1 Minor variations of Type IA

Such minor variations do not require any prior approval but must be notified by the holder within 12 months following implementation (“Do and Tell” procedure). A list of changes to be considered as minor variations of Type IA and the conditions that must be met for a change to follow a Type IA notification procedure are set out in the Variations Regulation and the annex to these

guidelines. However, certain minor variations of Type IA require immediate notification after implementation to ensure the continuous supervision of the medicinal product. Minor variations of Type IA do not require prior examination by the authorities before they can be implemented by the holder. The holder may group several minor variations of Type IA under a single notification, as established in Articles 7(2) and 13d(2) of the Variations Regulation. Specifically, two possibilities exist for the grouping of variations of Type IA: 1. The holder may group several minor variations of Type IA regarding the terms of one single marketing authorization provided that they are notified at the same time to the same relevant authority. 2. The holder may group one or more minor variations of Type IA to the terms of several marketing authorizations under a single notification provided that the variations are the same for all marketing authorizations concerned and they are notified at the same time to the same relevant authority. Review of Type IA will be carried out within 30 days following receipt by the RMS for mutual recognition procedure or by the national competent authority for purely national procedure. By day 30, the national competent authority will inform the holder of the outcome of its review. Where one or several minor variations of Type IA are submitted as part of one notification, the RMS/the national competent authority will inform the holder as to which variation(s) have been accepted or rejected following its review. The MAH must not implement the rejected variation(s). The same rule will apply for a Type IA variation review for a centralized procedure, carried out by the Agency without involvement of the rapporteur.

3. Legal framework for licensing medicines for human use in the EU

3.11.1.2 Minor variations of Type IB

Such minor variations must be notified before implementation. The holder must wait a period of 30 days to ensure that the notification is deemed acceptable by the relevant authorities before implementing the change (“Tell, Wait and Do” procedure). Within 30 days following the acknowledgment of receipt of a valid notification, the RMS/national competent authority will notify the holder of the outcome of the procedure. If the RMS/national competent authority has not sent the holder its opinion on the notification within 30 days following the acknowledgment of receipt of a valid notification, the notification will be deemed acceptable. 3.11.1.3 Major variations of Type II

Such major variations require approval of the relevant competent authority before implementation. As a general rule, for major variations of Type II, a 60-day evaluation period will apply. This period may be reduced by the national competent authority having regard to the urgency of the matter, particularly for safety issues, or may be extended to 90 days for variations listed in Part I of Annex V or for grouping of variations in accordance with Article 13d(2)(c) of the Variations Regulation. Within the evaluation period, the RMS/national competent authority may request the holder to provide supplementary information. The request for supplementary information will be sent to the holder together with a timetable stating the date by when the holder should submit the requested data and where appropriate the extended evaluation period. The procedure will be suspended until the receipt of the supplementary information. As a general rule, a suspension of 1 month will apply. For longer suspension the holder should send a

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justified request to the national competent authority for agreement. The evaluation of responses may take up to 30 or 60 days depending on the complexity and amount of data requested to the holder. The same rules will apply to Type II variations assessment for a centralized procedure. For the outcome, slight differences in procedure of notification between the national procedure, mutual recognition procedure, and centralized procedure exist. The procedure and time permitted in implementing these outcomes would follow different routes given the involvement of other Member States in the mutual recognition procedure/centralized application compared to one authority in the case of a nationally approved application. General rules apply to minor variations Type IB or major variations Type II: 1. Where the same minor variation of Type IB or the same group of minor variations or the same major variation of Type II or the same group of variations (as explained earlier) affect several marketing authorizations owned by the same holder, the holder may submit these variations as one application for “Worksharing.” Details about applications for “Worksharing” and procedure are given in the original guideline and would not be covered on this occasion. 2. Holders may group under a single notification the submission of several variations regarding the same marketing authorization, or group the submission of one or more major variation(s) of Type II with other minor variations regarding the same marketing authorization, provided that this corresponds to one of the cases listed in Annex III of the Variations Regulation, or when this has been agreed previously with the RMS, the national competent authority, or the Agency (as appropriate).

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3.12 Extensions An extension to or a modification of the existing marketing authorization will have to be granted by the Community. As established in Article 19 of the Variations Regulation (EC No. 1234/2008), such applications will be evaluated in accordance with the same procedure as for the granting of the initial marketing authorization to which it relates. The extension can either be granted as a new marketing authorization or will be included in the initial marketing authorization to which it relates. Annex I of the Variations Regulation sets out a list of changes to be considered as extensions. The following is a summary: 1. Changes to the active substance(s) include: (a) Replacement of the active substance(s) by a different salt/ester complex/derivative (with the same therapeutic moiety) where the efficacy/safety characteristics are not significantly different; (b) Replacement by a different isomer, a different mixture of isomers, or a mixture by an isolated isomer (e.g., racemate by a single enantiomer) where the efficacy/ safety characteristics are not significantly different; (c) Replacement of a biological substance or product of biotechnology with one of a slightly different molecular structure. Modification of the vector used to produce the antigen/source material, including a new master cell bank from a different source where the efficacy/safety characteristics are not significantly different; (d) A new ligand or coupling mechanism for a radiopharmaceutical; (e) Change to the extraction solvent or the ratio of herbal drug to herbal drug preparation where the efficacy/safety characteristics are not significantly different.

Evidence to confirm that no change in the pharmacokinetics/pharmacodynamics and/ or toxicity, which could significantly change the safety/efficacy profile, should be provided; Otherwise to be considered as a new active substance. 2. Changes to strength, pharmaceutical form, and route of administration include: (a) Change of bioavailability; (b) Change of pharmacokinetics, e.g., change in rate of release; (c) Change or addition of a new strength/ potency; (d) Change or addition of a new pharmaceutical form; (e) Change or addition of a new route of administration. Clinical data (safety/efficacy), pharmacokinetics, preclinical (e.g., local toxicology), if justified, including bioavailability studies, might need to be provided. Furthermore, on a case-by-case basis, biowaiver may be considered. Extension applications must be submitted to all Member States concerned, to the national competent authority, or to the Agency (as appropriate).

4. Conclusion The legal frame work covering the requirements and eligibility for marketing authorization of medicinal products in EU, ensuring compliance with the current EU standard for quality, safety and efficacy is well set out. In this chapter introduction to the Article, and regulations issued by the EU along with supporting publications explaining the legal requirements and procedures followed and how can they be implemented is made. This will help regulatory affair and technical professionals to determine the strategy of registration and market

References

penetration of medicinal product into different countries of EU and ways of achieving their goals. Regarding procedures, the decentralized route is the most common, whereby marketing authorization of the same medicinal product in more than one EU country at the same time through one procedure and one application can be made. Procedure for national application is still followed by some applicants for certain marketing strategy with option of mutual recognition into other EU countries once registered. This will take longer time to achieve compared to the decentralized procedure. However these different options are still applicable and available, providing the required flexibility for the applicants to follow.

Acknowledgments As this chapter describes regulatory and legal rules. The language must be same as describes by authorization bodies. Therefore, I would like to acknowledge EMA and other regulatory bodies for the information stated on respective websites for public knowledge. Readers are requested to check latest updates in rules and regulations before preparing application.

References [1] EC, “https://ec.europa.eu/info/about-european-commission/organisational-structure/how-commissionorganised_e,”. [2] “https://ec.europa.eu/info/departments,” [3] “https://ec.europa.eu/info/departments/consumershealth-agriculture-and-food_en,”. [4] “https://ec.europa.eu/info/departments/health-andfood-safety_en,”. [5] EMA, “http://www.ema.europa.eu/ema/index.jsp? curl¼pages/about_us/document_listing/document_ listing_000426.jsp&mid¼,”. [6] CHMP, “http://www.ema.europa.eu/ema/index. jsp?curl¼pages/about_us/general/general_content_ 000094.jsp&mid¼WC0b01ac0580028c79,”. [7] http://www.ema.europa.eu/ema/index.jsp? curl¼pages/about_us/general/general_content_ 000537.jsp&mid¼WC0b01ac058058cb18, “PRAC,”. [8] http://www.ema.europa.eu/ema/index.jsp? curl¼pages/about_us/general/general_content_ 000262.jsp&mid¼WC0b01ac0580028dd8, “CVMP,”.

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[9] http://www.ema.europa.eu/ema/index.jsp? curl¼pages/about_us/general/general_content_ 000263.jsp&mid¼WC0b01ac0580028e30, “COMP,”. [10] http://www.ema.europa.eu/ema/index.jsp? curl¼pages/about_us/general/general_content_ 000264.jsp&mid¼WC0b01ac0580028e7c, “HMPC,”. [11] http://www.ema.europa.eu/ema/index.jsp? curl¼pages/about_us/general/general_content_ 000266.jsp&mid¼WC0b01ac05800292a4, “CAT,”. [12] http://www.ema.europa.eu/ema/index.jsp? curl¼pages/about_us/general/general_content_ 000265.jsp&mid¼WC0b01ac0580028e9d, “PDCO,”. [13] https://www.hma.eu/cmdh.html, “CMDh,” [14] https://www.hma.eu/156.html. [15] https://eur-lex.europa.eu/LexUriServ/LexUriServ. do?uri¼OJ:L:2001:311:0067:0128:en:PDF, “Directive 2001,”. [16] https://ec.europa.eu/health/sites/health/files/files/ eudralex/vol-1/reg_2004_726/reg_2004_726_en.pdf, “Reg726,”. [17] https://ec.europa.eu/health/documents/eudralex_ en), “EudraLex,”. [18] https://ec.europa.eu/health//sites/health/files/ files/eudralex/vol-2/2012-06_gpr.pdf. [19] http://www.hma.eu/abouthma.html. [20] http://www.hma.eu/fileadmin/dateien/Human_ Medicines/CMD_h_/procedural_guidance/ Application_for_MA/Multi_App_MRP_DCP_2007_ 06_Rev3.pd), “CMD recommendation DCP 2007,”. [21] http://www.hma.eu/216.html,Paediatric use,”. [22] https://ec.europa.eu/health//sites/health/files/ files/eudralex/vol-1/com_2006_133/com_2006_133_ en.pdf. [23] https://ec.europa.eu/health/sites/health/files/files/ eudralex/vol-2/b/update_200805/ctd_05-2008_en. pdf. [24] http://www.ich.org, “ICH,”. [25] https://www.ema.europa.eu/en/documents/ scientific-guideline/guideline-investigationbioequivalence-rev1_en.pdf, “Bio2010,”. [26] http://ec.europa.eu/health/files/eudralex/vol-2/c/ guideline_14-11-2007_en.pdf, “GDL sig benefit,”. [27] http://ec.europa.eu/health/files/eudralex/vol-2/c, “New Therapeutic indication,”. [28] http://ec.europa.eu/health/files/eudralex/vol-2/c/ switchguide_160106_en.pdf, “change classs of supply,”. [29] https://ec.europa.eu/health/sites/health/files/files/ eudralex/vol-1/reg_2008_1234_cons_2012-11-02/reg_ 2008_1234_cons_2012-11-02_en.pdf, “Variation,”. [30] https://ec.europa.eu/health/sites/health/files/files/ eudralex/vol-1/reg_2012_712/reg_2012_712_en.pdf, “amending Var,”. [31] esubmission.ema.europa.eu/eaf/index.html.

C H A P T E R

4 Clinical considerations on micro- and nanodrug delivery systems Pramil Tiwari1, Vivek Ranjan Sinha2, Randeep Kaur2 1

Department of Pharmacy Practice, National Institute of Pharmaceutical Education & Research (NIPER), S.A.S. Nagar, Punjab, India; 2University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India bioavailability, high first-pass metabolism, and fluctuations of drug levels in plasma [2]. These constraints and drawbacks of traditional drug delivery systems can easily be overcome by controlling the delivery of APIs by incorporating them into micro- or nanoparticles. These encompass microemulsions, nanoemulsions, solid lipid nanoparticles (SLNs), nanostructured lipidic carriers (NLCs), polymer lipid hybrids or complexes (PLH), nanocapsules, metallic nanoparticles, polymeric microparticles, polymeric nanoparticles, liposomes, transfersomes, ethosomes, and niosomes. While incorporating drugs into these micro- and nanoparticles, targeted delivery is achieved in a controlled manner and unwanted side effects can easily be avoided. Despite these benefits, micro- and nanoparticles also increase bioavailability, prevent fast degradation as well as clearance of drugs from the body, and increase the concentration of drugs at the target sites, thereby lowering doses. As a result, maximum therapeutic effect and minimum toxic effects can be achieved [3]. So, due to these reasons, nowadays, researchers are

1. Introduction Over the past few years, an unrivaled increase in research innovations in the area of nanotechnology in medicine, more specifically in drug delivery, has been evidenced. Micro- and nanoparticles in drug delivery are in the size range of 10 nme1000 mm and comprise at the minimum two components, namely active pharmaceutical ingredients (APIs) and inert excipients, though the nanoparticle formulation of only APIs is also achievable. These micro- and nanoparticles are often associated with special functions such as treatment, prevention, and/or diagnosis of diseases. These are also termed smartdrugs or theranostics [1]. One of the major challenges in the treatment of various diseases is the delivery of APIs at target site. Drug delivery through traditional systems (such as emulsions, suspensions, and solutions) is thought to be less effective, having poor biodistribution of drugs and the absence of selectivity. These systems possess limitations such as high dose, relatively lower

Drug Delivery Trends https://doi.org/10.1016/B978-0-12-817870-6.00004-3

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mainly focusing their research on the development of micro- and nanoparticle-based drug delivery systems. After achieving promising results in preclinical studies, these drug delivery systems are subjected to clinical trials, which are regulated by the US Food and Drug Administration (US FDA). Clinical trials are systematic studies and are considered to be the best medical approach that works for specific illnesses and/or groups of people. Clinical trials generate blue ribbon data that are important for healthcare. Thus these clinical studies follow rigid scientific guidelines that assure patients and also help in achieving trustworthy results of clinical trials. Clinical trials are the final stage of an interminable and thoughtful research and development methodology or strategy [4]. This chapter offers an overview of clinical trials and an understanding of various types of micro- and nanodrug delivery systems and their applications. The authors have summarized the current status of various products based on the aforementioned drug delivery systems at different phases of clinical trials. Regulatory concerns regarding nanotechnology-derived products have also been discussed, albeit in brief.

2. Outline of drug development The US FDA has been describing and managing the prevailing pathway to the development of drugs and their approval. The agency places heavy importance primarily on safety and then on efficacy. The main purpose of clinical trials is to evaluate safety and maximum tolerated dose of drug, pharmacokinetics, and pharmacodynamic behavior of drug in humans, and also drugedrug interactions. When investigational drugs show promising results in preclinical studies, investigational new drug applications are submitted to the US FDA by drug sponsors or sponsor investigators. These applications give detailed information regarding the qualifications of investigators, data on preclinical

studies of drugs, and appeals to federal statutes to transport unapproved drugs nationwide. Once approval is granted, drugs are subjected to phase IeIII clinical trials. If after these phases, drugs are found to be safe and effective in the designed population, drug sponsors or sponsor investigators can file a new drug application to the US FDA. Then, the US FDA with the involvement and recommendation of an external panel/ committee thoroughly analyzes the results of phases IeIII and decides whether to grant an indication for drugs to be marketed. After passing the phase III trial, drugs reach the phase IV trial where again safety and efficacy in the designed population are observed. The four phases of clinical trials are explained here in brief (Fig. 4.1). Phase I trials are also known as “doseescalation” and “human pharmacology” studies. These trials are performed in smaller numbers of healthy and/or diseased human beings. Phase II trials are also known as “therapeutic exploratory” trials. These are performed in a small number of humans having the specific disease of interest to evaluate the safety, pharmacokinetics, and pharmacodynamics of investigational drugs. These phase II trials also include studies related to optimization of dose, dosing frequency, and route of administration that are crucial for the preparation of phase III trials. When drugs pass the phase I and II trials, they enter into phase III trials. The phase III trial is also known as a “therapeutic confirmatory,” “pivotal,” or “comparative efficacy” trial. This phase III trial is done in diverse target patients (not more than 300e3000 people) to confirm efficacy and to evaluate common adverse reaction incidences. Once the US FDA approves a drug, then phase IV clinical trials are done. Phase IV clinical trials are also known as “postmarketing” or “therapeutic use” studies. These phase IV trials are done on FDA-approved drugs to evaluate rare adverse reactions, cost effectiveness, and drug effectiveness in particular diseases and populations. Therefore phase IV trials are often regarded as observational studies [4].

3. Micro- and nanoparticles in drug delivery

FIGURE 4.1

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Different phases of clinical trials.

Micro and Nanoparticles as Drug Delivery Systems Vesicular

Non-vesicular

Liposomes (15 nm-500 nm)

Microemulsions (