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Preface
Hello fellow scientists! We would like to
thank you for reading the new and improved
second edition of our book, Nonclinical
Development of Biologics, Vaccines and Spe-
cialty Biologics.
This edition focuses the earlier work and
provides updates and new information
including significant advances in science and
regulatory climate. These developments
highlight not only the rapid pace of scientific
innovation but also the unwavering
commitment to improving global health
outcomes. This new edition aims to provide
a comprehensive resource for navigating the
complexities of nonclinical development in
this dynamic landscape.
Technological advances in vaccines, spe-
cifically the approval of the first mRNA
vaccines, allowed a response to the COVID-
19 pandemic that was unprecedented in its
speed, effectively saving millions of lives. In
large part, the speed with which these vac-
cines were developed was enabled by close
collaboration with health authorities and
new regulatory guidelines that included a
more widespread acceptance of a platform
approach, allowing development programs
to be more streamlined.
New cell and gene therapies represent
another frontier in the field of biologics, of-
fering the potential to cure previously
untreatable conditions. The development of
these therapies requires innovative nonclin-
ical strategies to address unique safety and
efficacy challenges.
The adoption of new approach methods
(NAMs), including advanced in vitro models
and computational methods, has enhanced
our ability to predict the safety and efficacy
of biologics. These methods, combined with
improved animal models and cutting-edge
analytical techniques, provide a more
comprehensive and accurate assessment of
new therapies.
The editors sincerely hope readers appre-
ciate the insights provided by all the subject
matter experts who took part in authoring
the new edition of our book. The content was
specifically selected to be a comprehensive
source of the most up-to-date science and
regulatory guidance concerning biologics,
vaccines, and specialty biologics for pro-
fessionals and nonprofessionals alike.
xi
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Acknowledgments
Writing a book is a monumental task that
requires dedication, passion, and collabora-
tion. We are grateful to the authors for their
willingness to share their expertise and
engage in constructive dialogue with us and
with each other. We hope that this book will
serve as a valuable resource and inspire
further innovation in these fields.
Thank you for your contributions and for
making this book possible.
xiii
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Development of
biopharmaceuticals
SECTION I
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1
Overview of biopharmaceuticals
and comparison with small-molecule
drug development
Christina de Zafra
1
, Eric Harstad
1
and Amy Kim
2
1
Drug Safety Research & Development, Pfizer Research & Development, Pfizer Inc., South San
Francisco, CA, United States;
2
Oncology Research, Pfizer Oncology Division, Pfizer Inc., South
San Francisco, CA, United States
OUTLINE
Introduction 3
Routes of administration 6
Nonclinical species for toxicology testing 7
Carcinogenicity assessment 9
Best practices in toxicology program
design in the wake of the COVID-19
pandemic 9
Classes of biopharmaceuticals 11
References 14
Introduction
The history of biopharmaceuticals was extensively reviewed in the first version of this
book so will be more briefly summarized in this version. The use of biologic therapies as early
as the 1920s started with the administration of “serum therapy” and with the use of immu-
noglobulin preparations derived from human placenta and plasma to treat a variety of infec-
tious diseases. Although these approaches yielded clinical successes, they were often
CHAPTER
3
Nonclinical Development of Biologics, Vaccines and
Specialty Biologics, Second Edition
https://doi.org/10.1016/B978-0-443-13344-2.00012-2
© 2025 Elsevier Inc. All rights are reserved, including those for text
and data mining, AI training, and similar technologies.
associated with a risk of immunological toxicities (Berger, 2002; Keller and Stiehm, 2000).
Since the advent of recombinant DNA technology in the 1970s, genetically engineered prod-
ucts have been designed to address a multitude of health conditions via approaches including
monoclonal antibodies, vaccines, and cell and gene therapies. Recombinant DNA technology
enabled the mass production of proteins and antibodies using living cells (bacterial, yeast,
plant, insect, or mammalian) and well-defined bioprocess methods. The resulting products
have a defined specificity and uniformity, which is a vast improvement over previous
methods of extraction and purification of proteins from human or animal blood and tissues.
Recombinant DNA-derived medicinal products are often interchangeably referred to as “bio-
pharmaceuticals,”“biotherapeutics,”“biologicals,” or “biologics.”
While well over 1000 small molecule drugs have been approved by the FDA since the
1950s (Munos, 2009), approximately 500 biotherapeutic drugs have received regulatory
approval (Walsh and Walsh, 2022). Since the first biotechnology product, human insulin,
was approved in 1978 (Reichert and Paquette, 2003), 541 individual biopharmaceutical prod-
ucts (by trade name) have received regulatory approval in the United States and European
Union, containing 435 distinct active biopharmaceutical ingredients. Taking into account
that 98 products have been withdrawn from the market, the number of currently approved
individual biopharmaceutical products is approximately 443 (Walsh and Walsh, 2022).
The key differences between small molecule and biologic therapeutics, as well as vaccines,
are summarized in Table 1.1 illustrating the vast differences in nature of each, which of course
leads to unique manufacturing, safety testing, and regulatory considerations.
Historically, the selection of a small molecule for advancement to clinical development
included selectivity for the intended target with minimal off-target toxicities. Additionally,
the synthesis of small-molecule drugs is tightly controlled, and both the active pharmaceu-
tical ingredient (API) and final drug product are regulated by health authorities. The final
drug product contains a high-purity API with set limits dependent upon the stage of devel-
opment for an allowable percentage of process impurities, genotoxic impurities, elemental
impurities, and residual solvents (ICH, 2006, 2011) the safety of which may also require addi-
tional toxicity assessment. The drug-like properties of a small molecule compound are
defined by its physicochemical characteristics (solubility, permeability, and stability), struc-
ture, molecular weight, lipophilicity, pK
a
, polar surface area, shape and reactivity; and by
its biochemical attributes such as metabolism, drugedrug interactions, and cellular uptake
and transport (Curatolo, 1998; Kerns, 2008). These structural, physicochemical, and biochem-
ical properties form the basis of a small molecule compound’s bioavailability, distribution,
and ability to enter a cell and/or nuclear membrane by passive diffusion or active transport
and bind a specific biological target to elicit its intended pharmacologic action. However, the
properties that make a small molecule desirable for its intended pharmacology may also
contribute to its off-target toxicity. Most small molecules being developed today are still opti-
mized for oral administration.
Developers of both small molecules and biopharmaceutical drugs have sought to improve
pharmacokinetic properties during discovery and development. In contrast to bio-
pharmaceuticals for which a long half-life is desirable to reduce frequency of parenteral (typi-
cally intravenous [IV]) administration, a longer half-life for small molecule drugs can be
highly undesirable as it may lead to interaction with other drugs rendering one or both of
them less efficacious and/or more toxic (Kerns, 2008). Given the potential for off-target
1. Overview of biopharmaceuticals and comparison with small-molecule drug development4
I. Development of biopharmaceuticals
TABLE 1.1 Comparison of characteristics of small molecule and protein-based biopharmaceutical
therapeutics.
Characteristic Small molecules Biologics Vaccines
Physicochemical
properties
• Typically less than 1000 Da
(Da)
• Defined structure
• Generally higher stability
• Higher tissue/cell
permeability
• Usually over 1 kDa (kDa)
• Structure may or may not
be completely defined or
known
• Complex, may be sensitive
to heat, light, or other
stressors
• Low tissue/cell
permeability
• Multiple: peptide, protein,
conjugates, complexes,
virus-like particles, live or
attenuated virus or
bacteria, viral vectors,
DNA, mRNA
• Adjuvants: Aluminum
salts, oligonucleotides,
lipids, saponins, and
emulsions
Pharmacokinetic
properties
• Oral and parenteral routes
• Typically rapid absorption;
may be subject to influx/
efflux
• Cleared as parent or
metabolite via hepatic,
renal, or pulmonary routes;
may have active or reactive
intermediates or
metabolites
• Intra- and extracellular
targets
• Short half-life
• Typically parenteral route
(IV, SC)
• Slow absorption by non-IV
routes; limited active
transport interactions
• Proteolytic and target-
mediated elimination;
catabolized to amino acids
• Typically extracellular
targets
• Long half-life
• Typically parenteral route
(IM, SC), some mucosal
(oral, inhalation)
• Traditional PK (i.e.,
ADME) not assessed;
rather, PD assessment of
vaccine activity serves to
confirm exposure
• Biodistribution studies may
be conducted (e.g., viral
vectored vaccines)
Production/
manufacturing
• Chemical synthesis of
varying complexity
• Single entity, high chemical
purity
• Produced through
biotechnology typically
using a host cell line or
other living cells
• Heterogenous mixture
including host cell- and
process-derived impurities,
possibly structural variants
• Highly susceptible to
changes in production
process and environmental
conditions
• Many critical process steps
• Various depending on
vaccine format
• Complex manufacturing
and release of vaccine
material
Relevant regulatory
guidance(s)
• Primarily ICH guidelines;
M3(R2), M7, M12,S1A-C,
S2, S7A-B, S9, S10
• Primarily ICH guidelines
(see Chapter 12); M6, S6,
S7A-B, S9, S12
• WHO, ICH S5, EMA, and
country-specific guidelines
(see Chapter 8, Table 1.1)
Nonclinical species
for toxicology
testing
• 2 species (rodent and
nonrodent) based on
exposure, metabolism, and
pharmacology (if known)
• 1e2 relevant species, based
on target expression and
cross-reactivity/activity,
pharmacology
• Typically 1 relevant species
based on immune response
or viral replication,
potentially waived if
platform data are available
Introduction 5
I. Development of biopharmaceuticals
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