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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5608_Библиотеки_им_академика_М_И_Перельмана.pdf
Bioprocessing,
Bioengineering
and Process
Chemistry in the
Biopharmaceutical
Industry
Kumar Gadamasetti
Stephen A. Kolodziej
Editors
Using Chemistry and
Bioengineering to Improve the
Performance of Biologics
Bioprocessing, Bioengineering and Process
Chemistry in the Biopharmaceutical Industry
Kumar Gadamasetti • Stephen A. Kolodziej
Editors
Bioprocessing,
Bioengineering and Process
Chemistry in the
Biopharmaceutical Industry
Using Chemistry andBioengineering
toImprove thePerformance ofBiologics
Editors
Kumar Gadamasetti
Certum Bio
San Francisco, CA, USA
Stephen A. Kolodziej
Bioprocess Research and Development
Biotherapeutics Pharmaceutical Sciences
Pzer, Inc.,
Chestereld, MO, USA
ISBN 978-3-031-62006-5 ISBN 978-3-031-62007-2 (eBook)
https://doi.org/10.1007/978-3-031-62007-2
© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature
Switzerland AG 2024
This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether
the whole or part of the material is concerned, specically the rights of translation, reprinting, reuse of
illustrations, recitation, broadcasting, reproduction on microlms or in any other physical way, and
transmission or information storage and retrieval, electronic adaptation, computer software, or by similar
or dissimilar methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specic statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in this book
are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the
editors give a warranty, expressed or implied, with respect to the material contained herein or for any
errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional
claims in published maps and institutional afliations.
This Springer imprint is published by the registered company Springer Nature Switzerland AG
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
If disposing of this product, please recycle the paper.
KG would like to dedicate this volume to his
parents, Rao and Devi, and children, Stuthi
and Pratik, and to all those who work
relentlessly towards nding solutions in
alleviating the pain and suffering of patients.
SAK would like to dedicate this book to his
wife Mary and his children Rebecca, Eric
and Brian.
Foreword
Biotherapeutics are driving a remarkable healthcare revolution, propelling medicine
into new frontiers and transforming the landscape of patient care. These advancements build on decades of success with monoclonal antibodies and are being further
guided by technological innovations catalyzing novel therapeutic modalities. In parallel, important fundamental scientic discoveries are shedding new light on biochemical processes underlying human disease and illuminating new targets for
therapeutic intervention. It is an exciting time for biotechnology, a spirit that the
authors have captured in the current volume, which eloquently describes both the
current state of affairs and the advancements in bioprocess engineering related to
biotherapeutic development.
Biotherapeutics discovery, development, and manufacturing take a village,
including academic researchers who make seminal scientic discoveries, entrepreneurs who start biotechnology companies based on this knowledge, venture capitalists who fund these companies, pharmaceutical companies who provide expertise
and resources throughout, and regulatory agencies which oversee clinical trials and
approvals. A thriving ecosystem relies on stakeholders throughout the value chain,
where lines and roles are becoming blurred, particularly as contract organizations
become more prolic and enable outsourcing of activities that have historically
been infrastructure and resource heavy. However, despite all of the advancements
made and partnerships forged, the cost of developing drugs is still prohibitively
expensive and the timelines excruciatingly long. Researchers in academia and
industry have created tools to accelerate early-stage drug screening and characterization efforts, yet signicant bottlenecks and costs exist with manufacturing drug
candidates at scale, especially for new therapeutic modalities.
Several chapters of this volume are devoted to innovations in biotherapeutics
manufacturing including scalability of DNA synthesis, cell culture technologies,
and considerations related to more complex therapeutics beyond monoclonal antibodies such as multi-specic and fusion proteins, drug conjugates, gene therapies,
vaccines, and engineered cells. Complementing the discussion are chapters focused
on data analytics, bioinformatics approaches for assessing developability, and regulatory considerations which are a key part of the manufacturing landscape. Also
vii
viii
Foreword
included are deep dives on some of the twenty-rst century’s most exciting topics
under the broad theme of synthetic biology, which is enabling researchers to leverage engineering principles to construct new biological systems, molecules, and
organisms with specic functionalities.
A convergence of scientic breakthroughs, technological advancements, and
interdisciplinary collaboration has propelled biotherapeutics to the forefront of
modern medicine. While innovations in biotherapeutics development and manufacturing discussed in this volume are a glimpse into the extraordinary progress being
made in this dynamic eld, as personalized medicine and targeted interventions
continue to shape how we approach and conquer disease, it is imperative to foster
continued investment in research, development, and regulatory frameworks that
ensure the safety, efcacy, and accessibility of these transformative therapies. Thus,
I highly recommend this book to those desiring education in these key areas.
Jennifer R.Cochran
Senior Associate Vice Provost for Research, Macovski Professor of Bioengineering
and (by courtesy) Chemical Engineering, Stanford University, Stanford, CA, USA
Limitless possibilities are unleashed with continuing advances in biochemical
discovery applied to human health. Within the context of the 2019 Covid pandemic,
we witnessed an industry galvanized with a single purpose to pursue new medicines
and vaccines to bring an end to the outbreak. While many of the approaches used
were based on established technologies, we also saw disruptive solutions implemented with RNA technologies, scale-out strategies, and delivery solutions that
have far-reaching applications.
Vaccines once again demonstrated the transformative nature of their application
in providing a route out of the pandemic. Indeed, vaccination is considered one of
the most successful public health interventions of all time and has undoubtedly
resulted in preventing millions of deaths. But those applications are not limited to
vaccines and have far-reaching potential in the eld of therapeutics, including cell
and gene therapies, with the promise of treating chronic or acquired diseases. To
date, we have seen the licensure of several gene therapies, against beta-thalassemia,
lymphoma and leukemia, inherited retinal disorders, and cerebral adrenoleukodystrophy. These are examples of early successes, but there are countless others that do not reach the end-point, whether for reasons of cell-specic targeting or
durability of response; understanding this will be critical to advancing the eld.
Our comprehension of cancer and novel mechanisms to identify, target, and kill
these cells has also led to the development of bi- and tri- specic antibodies, and
antibody-drug conjugates. The complexity of these new molecules, from their
design, stability, expression, and purication, should not be underestimated. While
antibodies have historically benetted from platform processing, these new entities
require a degree of customization not previously witnessed.
For the biochemical engineer or process scientist, the eld has become a much
more interesting world, both in the challenges and the tools they must utilize to
deliver the promise of tomorrow’s medicines. Tools such as synthetic biology and
Crisper technologies allow a degree of cellular manipulation and editing for the
Foreword
ix
identication of new drug targets, biomarkers, and identication of mechanisms
leading to drug resistance. In all these tool sets unlock novel strategies for the treatment of infectious and non-infectious diseases. However, with such novel advancements, the regulatory framework will have to be negotiated and the role of our
scientists will be to collate the data required to license these approaches, and a voice
of advocacy in driving their adoption, thus the need of developing true expertise in
the eld.
Perhaps the most weighted consideration in any development plan is the cost of
goods. Considering which market these products will launch and how to best
achieve distribution to maximize utility is a key aspect of any target product prole.
While rst-generation vaccines may have achieved the lowest cost possible; multiproduct, multi-valency vaccines increase these costs. The problem is further compounded in the therapeutic space, especially in cell therapies where the process is
affected by high labor costs and low volume production. There are two possible
strategies that could be executed in a complimentary manner—operating in a globalized manner to take advantage of localized distribution chains and labor costs, or
to create manufacturing solutions that break the economies of scale model. It is
possible that a little of both will be required, which means that tech transfer and
regionalization will still be critical to successful execution.
I recommend this book to those in academia and industry in the translational sciences and process engineering. It covers a wide range of pertinent topics described
above while giving the reader a focused context of current technologies and future
trends, and I commend the authors on an excellent summary of an array of difcult topics.
Tarit K.Mukhopadhyay
Vice President, Head of Infectious Disease and Vaccines Discovery, Merck & Co.,
Rahway, NJ, USA
The biopharmaceutical industry has seen rapid advancements over the past four
decades, dating back to the development of recombinant insulin. The signicant
change and progress in that time has been breathtaking, and the editors and authors
of this volume have captured recent advances in the eld which both capture our
past and simultaneously look forward to future advancements.
This volume highlights the wide variety of modalities that are currently being
developed within the industry. The authors begin with a discussion of the optimization and continued development of protein-based biotechnology products (mAbs,
bi-specics, etc.) and focus on concerns around cellular output and process intensication. This is critical, for as a more mature industry we need to deliver on the
hope of biotechnology products in a global, equitable manner. Subsequent chapters
review novel therapies including AAV-based gene therapies, CAR-T, ADCs, and
mRNA-LNPs, emphasizing the continued evolution of modalities. This diversity of
products demonstrates an expanding toolkit of potential therapeutics with which to
address unmet medical needs, as well as it shows that, as a eld, we can both continuously learn and apply expertise and talents to new compounds. In addition to
highlighting developments in the creation of novel products, there are several
x
Foreword
chapters on areas which compliment the discussion of biotechnology product and
process development, specically oligonucleotide synthesis, advances in bioconjugation, informatics, regulatory strategies, continuous manufacturing, and
technical transfer all of which are required for thoughtful development and implementation of biopharmaceutical products.
One aspect that this volume highlights is the continued intersection of protein
chemistry, cell biology, process engineering, and analytical characterization that is
required to develop these complex compounds and their scalable and controlled
manufacturing processes. While these disciplines were combined at the initiation of
the eld of biotechnology, the level of sophistication and understanding of production cell biology (metabolism, genetics, optimal growth, and expression conditions)
has expanded signicantly providing us with condence that these products can be
produced at lab scale, as well as at production scale, in a manner that is predictable
and sustainable. The principles and experiences associated with scale-up of monoclonal antibodies, developed over the past 30years, can be applied to modalities
which are still emerging such as potential CRISPR-based therapeutics for gene editing. Again, as technologies evolve, so do therapies, enabling patients to slowly
migrate, for example, from the management and treatment of hemophilia-based disorders with Factor VIII and Factor IX to potential AAV-based cures. The modalities
are remarkably different but the fundamentals of molecular design, cell culture,
process design, and manufacture of aseptic injectables are the same.
Looking forward, we can be assured that there will be challenges with new
modalities as well as increased scale and production of existing products. With
these challenges, however, we can be condent that the foundation of biology,
chemistry, and engineering described in this volume will enable continued success
in the development and implementation of novel therapies for patients across
the globe.
Nicholas W.Warne
Biotherapeutics Pharmaceutical Sciences, Pzer, Inc., Cambridge, MA, USA
Preface
Drug development in the pharmaceutical and biopharmaceutical industry entails
discovery, pre-clinical and clinical development and market launching of the drug
under regulatory constraints. The previous two volumes (Process Chemistry in the
Pharmaceutical Industry—1999 and 2008) by one of the authors (Gadamasetti)
were dedicated to the development of the drug substance (active pharmaceutical
ingredient), and in particular, the introduction of biologics (monoclonal antibodies)
development to the process technologists and process development community in
the pharmaceutical industry made a signicant impact and has been an eye-opener
for some of the readers. Given the explosive growth of biologics around the turn of
the millennium on the need-basis of the technologies and the applications to address
the patient population demands, it became relevant to discourse the need to understand and share the information on biologic drugs, bioprocessing and the bioengineering in developing the biologic drug to bring it to patients. The editors sense the
compelling need to share the various aspects of technologies and the process of
biologic drug development, CMC regulatory aspects and the pathways to bring the
biologic drugs to patients to minimize the pain and suffering and maximize the
outcomes.
The genesis and the devastating rapid spread of the pandemic in 2019 have challenged the global scientic community outlook to embrace and adapt the methods
for the speedy development of vaccines to bring them to the patient population and
the paradigm shift of speedy discovery and the development has once again proved
the strength of unity among the researchers, developers and manufacturers alike, in
addressing the challenges with sense of urgency, globally.
The work in this volume embraces the inclusivity of various disciplines to jointly
undertake the problem-solving issues in discovering and developing the need-based
biological medicines to market the drugs for alleviating the pain and suffering of the
patients. The topics and subject material were deliberately chosen to cover a wide
range of topics by global expertise: synthetic biology, oligo nucleotides and DNA
synthesis, CAR-T and CRISPR technologies and applications, biosimilars, bioprocessing, process engineering, gene therapy and vaccines, fusion proteins,
xi