Biopharmaceutical Manufacturing, Volume 1: Regulatory Processes

448 Pages·2021·20.097 MB·English

by  Sarfaraz K. Niazi, Sunitha Lokesh

Biopharmaceutical
Manufacturing, Volume 1
Regulatory processes

Biopharmaceutical
Manufacturing, Volume 1
Regulatory processes
Sarfaraz Niazi
University of Illinois, Chicago, IL, USA
Sunitha Lokesh
Pharmaceutical Scientist LLC, Deerfield, IL, USA
IOP Publishing, Bristol, UK
ªIOPPublishingLtd2021
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ISBN 978-0-7503-3175-3(ebook)
ISBN 978-0-7503-3173-9(print)
ISBN 978-0-7503-3176-0(myPrint)
ISBN 978-0-7503-3174-6(mobi)
DOI 10.1088/978-0-7503-3175-3
Version:20211201
IOPebooks
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PublishedbyIOPPublishing,whollyownedbyTheInstituteofPhysics,London
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ToDrSarahYim,whosehumility,scientificwisdom,andvisionhelpmanymindsgrow
at the FDA and in the biosimilars community. —Sarfaraz K Niazi
Iamthankfultomyfatherforencouragingmetobeacuriousscientistandmyhusband
for supporting me to practice my passion. —Sunitha Lokesh

Contents
Preface xvii
Acknowledgments xxxi
Author biographies xxxii
1 Introduction to biopharmaceuticals 1-1
1.1 Overview 1-1
1.1.1 Biosimilars 1-4
1.1.2 Intellectual property 1-4
1.1.3 Regulations 1-5
1.2 Biopharmaceutical molecules 1-7
1.2.1 Overview 1-7
1.2.2 Molecular mechanism 1-8
1.2.3 Therapeutic classification 1-9
1.2.4 Hormone peptide drugs 1-9
1.2.5 Human hematopoietic factor 1-10
1.2.6 Human cytokines 1-10
1.2.7 Human plasma protein factor 1-11
1.2.8 Human bone formation protein 1-11
1.2.9 Recombinant enzymes 1-11
1.2.10 Antibodies 1-11
1.3 Protein structure and properties 1-14
1.3.1 Primary structure 1-14
1.3.2 Secondary structure 1-18
1.3.3 Tertiary structure 1-22
1.3.4 Quaternary structure 1-23
1.3.5 Post-translational modification (PTM) 1-23
1.3.6 Association and aggregation 1-29
1.4 Pharmacokinetic manipulations 1-29
1.4.1 Protein modification to increase the duration of action 1-30
1.5 Immunogenicity 1-31
1.5.1 The immune system 1-31
1.5.2 Antibodies 1-33
1.5.3 Antigens 1-33
1.5.4 Biopharmaceutical immunogenicity 1-34
1.5.5 Immunogenicity testing 1-36
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1.6 Recombinant expression 1-36
1.6.1 Understanding DNA and RNA 1-37
1.7 Gene and cell therapy 1-40
1.7.1 Gene editing 1-40
1.8 Conclusion 1-42
2 Antibody biopharmaceuticals 2-1
2.1 Overview 2-1
2.1.1 Naming 2-2
2.1.2 Commercial antibodies 2-3
2.2 The immune system 2-3
2.2.1 Innate immune system 2-11
2.2.2 Adaptive immune system 2-11
2.3 Monoclonal antibodies 2-11
2.3.1 Mode of action 2-13
2.4 Types of antibodies 2-16
2.4.1 Bispecific (BsAbs) 2-17
2.4.2 Fab fragments and single-chain antibodies 2-18
2.4.3 Humanized and chimeric mAbs 2-19
2.4.4 Affinity maturation 2-21
2.4.5 Antigenized antibodies 2-21
2.4.6 IgG1 fusion proteins 2-22
2.4.7 Drug or toxin conjugation 2-22
2.5 Development of antibodies 2-23
2.5.1 Endogenous method: single B-cell 2-23
2.5.2 Exogenous methods 2-23
2.5.3 Mouse hybridoma 2-24
2.5.4 Transgenic mice 2-27
2.5.5 Surface display libraries 2-28
2.5.6 Recombinant expression 2-34
2.6 Conclusion 2-35
2.7 Databases relevant to antibodies 2-35
3 Gene and cell therapy 3-1
3.1 Overview 3-1
3.2 Gene therapy 3-2
3.2.1 Methodologies 3-2
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3.2.2 Risks of gene therapy 3-5
3.2.3 Gene-editing technologies 3-6
3.2.4 Vector manufacturing 3-7
3.2.5 DNA vaccines 3-14
3.2.6 mRNA vaccines 3-18
3.3 Cell therapy 3-21
3.3.1 Types of cell therapies 3-22
3.3.2 CAR-T treatment (cellular immunotherapy) 3-23
3.3.3 Allogenic cell therapy 3-24
3.4 Regulatory considerations 3-26
3.4.1 Development and characterization of cell populations for 3-27
administration
3.4.2 Characterization and release testing of cellular gene therapy 3-30
products
3.4.3 Additional possible applications: radioisotopes or toxins 3-31
added to cell preparations
3.4.4 Vector production, characterization, and release testing 3-32
for gene therapy
3.4.5 Construction and characterization of vectors 3-32
3.4.6 Vector manufacturing system 3-32
3.4.7 Viral master banks 3-33
3.4.8 Lot-to-lot distribution vector testing and specifications 3-33
3.4.9 Issues in gene therapy related to specific vector classes 3-34
3.5 Conclusion 3-35
4 Formulation of biopharmaceuticals 4-1
4.1 Overview 4-1
4.2 Structural instability 4-2
4.2.1 Basis 4-2
4.2.2 Physical degradation 4-4
4.2.3 Chemical degradation 4-8
4.3 Formulation composition 4-19
4.3.1 Route of administration 4-19
4.3.2 Excipients and properties 4-21
4.3.3 Liquid formulations 4-25
4.3.4 Lyophilized formulations 4-26
4.4 Delivery routes 4-28
4.4.1 Intravenous 4-28
ix