21J. Geigert, The Challenge of CMC Regulatory Compliance for Biopharmaceuticals and Other Biologics,
DOI 10.1007/978-1-4614-6916-2_2, © Springer Science+Business Media New York 2013
In my conversations with senior management,
especially those who have moved recently from
the chemical drug side of the pharmaceutical
industry into the biologics side, I am asked
whether biologics are really different than chemical
drugs or is it just a perception that they are
different. And the question is understandable if
one has limited understanding of the challenges
imposed by these products. Biologics, when
directly compared to chemical drugs, (1) take
more staff to operate and control the manufacturing
processes, (2) have more demanding and
expensive QC release and stability tests, and (3)
have an extensive number of batch and testing
records for QA to review which takes QA longer
to release each batch of product.
Probably the strongest argument that biologics
are different than chemical drugs is from
the statements made by the regulatory authorities
themselves. As is shown in this chapter, in the
eyes of both the FDA and the EMA, biologics are
definitely different from chemical drugs. This is
not a perception, but a reality, and it is reflected
by the statements on their websites and in the
wording of the regulatory guidances that they
issue. Also, as is shown in this chapter, the three
major differences between biologics and chemical
drugs are discussed: (1) use of living source
materials to produce the biologic, (2) increased
complexity of biologic manufacturing processes,
and (3) increased complexity of the biologic molecules
themselves. Finally, in this chapter, an
2
As soon as you go into any biological process in any real detail, you discover it’s
open-ended in terms of what needs to be found out about it.
Joshua Lederberg, American molecular biologist,
Nobel Prize winner, 1925–2008
Abstract
It is shown that in the eyes of both the FDA and the EMA, biologics are
definitely different from chemical drugs. This is not a perception, but a
reality, and it is reflected by the statements on their websites and in the
wording of the regulatory guidances that they issue. Also, as is shown in
this chapter, the three major differences between biologics and chemical
drugs are discussed: (1) use of living source materials to produce the biologic,
(2) increased complexity of biologic manufacturing processes, and
(3) increased complexity of the biologic molecules themselves. Finally, in
this chapter, an explanation is presented of why biosimilar biological
products are best viewed as similar biologics and not as true generics.
Keywords
Biosimilars • Generics • FDA • EMA • WHO • Health Canada • ICH
• NDA • ANDA • BLA • Abbreviated BLA
Biologics Are Not Chemical Drugs
22 2 Biologics Are Not Chemical Drugs
explanation is presented of why biosimilar
biological products are best viewed as similar
biologics and not as true generics.
2.1 Regulatory Authorities Agree
The FDA and EMA regulatory authorities
clearly see the reality that biologics are not
chemical drugs. A glance at the statements on
their websites and a review of the wording in
their regulatory guidances for these products
show this. Furthermore, the ICH consensus
guidance documents add support to this regulatory
acceptance that biologics are different than
chemical drugs.
2.1.1 FDA’s Viewpoint on Differences
FDA embraces the reality that biologics are not
chemical drugs. On its introduction to biological
products website, the FDA openly discusses some
general differences between these two classes of
drugs [1].
Most drugs consist of pure chemical substances
and their structures are known. Most biologics,
however, are complex mixtures that are not easily
identified or characterized. Biological products
differ from conventional drugs in that they tend to
be heat-sensitive and susceptible to microbial contamination.
This requires sterile processes to be
applied from initial manufacturing steps.
The FDA website also has a location for frequently
asked questions about regulating biologic
products. On that website, one question that the
FDA addresses is as follows: “How do biologics
differ from conventional drugs?” [2]
10. How is the manufacturing process for a biological
product usually different from the process
for drugs? Because, in many cases, there is limited
ability to identify the identity of the clinically
active component(s) of a complex biological product,
such products are often defined by their manufacturing
processes. Changes in the manufacturing
process, equipment or facilities could result in
changes in the biological product itself and sometimes
require additional clinical studies to demonstrate
the product’s safety, identity, purity and
potency. Traditional drug products usually consist
of pure chemical substances that are easily analyzed
after manufacture. Since there is a significant
difference in how biological products are made,
the production is monitored by the agency from the
early stages to make sure the final product turns out
as expected.
Two guidance documents issued by FDA on
CMC content for Investigational New Drug
(IND) clinical applications, one for human gene
therapy [3] and the other for cell-based biologics
[4], reinforce the reality of the differences
between biologics and chemical drugs:
In order to deliver a safe and effective product,
human somatic cell therapies present many manufacturing
challenges. Some of these challenges
include the variability and complexity inherent in
the components used to generate the final product,
such as the source of cells (i.e., autologous or allogeneic),
the potential for adventitious agent contamination,
the need for aseptic processing, and the
inability to “sterilize” the final product because it
contains living cells. Distribution of these products
can also be a challenge due to stability issues and
the frequently short dating period of many cellular
products, which may necessitate release of the final
product for administration to a patient before certain
test results are available.
Thus, from the FDA viewpoint, biologics are
different from chemical drugs due to (1) the use
of living source materials to produce the biologic,
(2) increased complexity of the manufacturing
processes, and (3) increased complexity of the
products themselves.
2.1.2 EMA’s Viewpoint on Differences
The EMA embraces the reality that biologics are not
chemical drugs. The EU GMP Annex 2 guideline
on manufacture of biological medicinal substances
and products openly discusses the differences
between biologics and chemical drugs [5]:
The manufacture of biological medicinal products
involves certain specific considerations arising
from the nature of the products and the processes.
The ways in which biological medicinal products
are manufactured, controlled and administered
make some particular precautions necessary.
Unlike conventional medicinal products, which
are manufactured using chemical and physical
techniques capable of a high degree of consistency,
the manufacture of biological medicinal substances
and products involves biological processes and
232.1 Regulatory Authorities Agree
materials, such as cultivation of cells or extraction
of material from living organisms. These biological
processes may display inherent variability, so
that the range and nature of by-products may be
variable. As a result, quality risk management
(QRM) principles are particularly important for
this class of materials and should be used to
develop their control strategy across all stages of
manufacture so as to minimise variability and to
reduce the opportunity for contamination and
cross-contamination.
Since materials and processing conditions used
in cultivation processes are designed to provide
conditions for the growth of specific cells and
microorganisms, this provides extraneous microbial
contaminants the opportunity to grow. In addition,
many products are limited in their ability to
withstand a wide range of purification techniques
particularly those designed to inactivate or remove
adventitious viral contaminants. The design of the
processes, equipment, facilities, utilities, the conditions
of preparation and addition of buffers and
reagents, and training of the operators are key considerations
to minimise such contamination events.
A 2005 guidance document issued by EMA
on similar biological medicines reinforces the
reality of the differences between biologics and
chemical drugs [6]:
Biological medicinal products are usually more
difficult to characterise than chemically derived
medicinal products. In addition, there is a spectrum
of molecular complexity among the various products
(recombinant DNA, blood or plasma-derived,
immunologicals, gene and cell-therapy, etc.).
Moreover, parameters such as the three-dimensional
structure, the amount of acido-basic variants
or post-translational modifications such as the glycosylation
profile can be significantly altered by
changes, which may initially be considered to be
‘minor’ in the ;the monitoring of quality aspects.
Thus, the EMA, consistent with the viewpoint
of the FDA, agrees that biologics are different
from chemical drugs due to (1) the use of living
source materials to produce the biologic, (2)
increased complexity of the manufacturing processes,
and (3) increased complexity of the products
themselves.
2.1.3 ICH’s Position on Differences
While ICH is not a regulatory authority, the tripartite
guidances that are issued under this title
are consensus guidance documents accepted by
the FDA, EMA, and the Japanese Ministry of
Health Labor and Welfare (JMHLW). As the
ICH has attempted to develop consensus guidances,
they have had to face the reality of the
differences between biologics and chemical
drugs.
ICH has issued two consensus guidance
documents entitled “Specifications: Test
Procedures and Acceptance Criteria”; one is
specific for chemical drugs (ICH Q6A) and the
other is specific for biological products (ICH
Q6B). Owing to the differences between chemical
drugs and biologics, each document makes a
strong point of indicating in its scope that it
applies either only to chemical drugs or only to
biological products:
ICH Q6A [7]
This guideline addresses only the marketing
approval of new drug products (including combination
products) and, where applicable, new drug
substances; it does not address drug substances or
drug products during the clinical research stages of
drug development. This guideline may be applicable
to synthetic and semi-synthetic antibiotics and
synthetic peptides of low molecular weight; however,
it is not sufficient to adequately describe
specifications of higher molecular weight peptides
and polypeptides, and biotechnological/biological
products.
ICH Q6B [8]
The principles adopted and explained in this document
apply to proteins and polypeptides, their
derivatives, and products of which they are components
(e.g., conjugates). These proteins and polypeptides
are produced from recombinant or
nonrecombinant cell-culture expression systems
and can be highly purified and characterized using
an appropriate set of analytical procedures. The
principles outlined in this document may also apply
to other product types such as proteins and polypeptides
isolated from tissues and body fluids. To
determine applicability, manufacturers should consult
with the appropriate regulatory authorities.
A separate ICH Guideline, “Specifications:
Test Procedures and Acceptance Criteria for New
Drugs Substances and New Drug Products:
Chemical Substances” addresses specifications,
and other criteria for chemical substances.
ICH has also issued two consensus guidance
documents entitled “Stability Testing,” one for
chemical drugs (ICH Q1A(R2)) and one for biological
products (ICH Q5C). Owing to the differences
between chemical drugs and biologics,
24 2 Biologics Are Not Chemical Drugs
each document makes a strong point of indicating
in its scope that it applies either to chemical drugs
only or biological products only:
ICH Q1A(R2) [9]
The guidance addresses the information to be submitted
in registration applications for new molecular
entities and associated drug products.
Further guidance on new dosage forms and on biotechnological/biological
products can be found in
ICH guidances Q1C Stability Testing for New
DosageFormsandQ5CQualityofBiotechnological
Products: Stability Testing of Biotechnological/
Biological Products, respectively.
ICH Q5C [10]
The guidance stated in this annex applies to wellcharacterised
proteins and polypeptides, their
derivatives and products of which they are components,
and which are isolated from tissues, body
fluids, cell cultures, or produced using rDNA technology.
Thus, the document covers the generation
and submission of stability data for products such
as cytokines (interferons, interleukins, colony
stimulating factors, tumour necrosis factors),
erythropoietins, plasminogen activators, blood
plasma factors, growth hormones and growth factors,
insulins, monoclonal antibodies, and vaccines
consisting of well-characterised proteins or polypeptides.
In addition, the guidance outlined in the
following sections may apply to other types of
products, such as conventional vaccines, after consultation
with the appropriate regulatory authorities.
The document does not cover antibiotics,
allergenic extracts, heparins, vitamins, whole
blood, or cellular blood components.
2.2 Three Major Differences
of Biologics
The regulatory authorities do indeed state clearly
that biologics are not chemical drugs. The differences
that they identify will obviously be
reflected in the way that the regulatory authorities
evaluate and regulate the control of the biologics.
An understanding of the three major
differences gives an appreciation of why regulatory
authorities manage the biologics so differently
than chemical drugs: (1) use of living
source materials, (2) impact of the manufacturing
processes on the produced biologic, and (3)
complexity of the produced biologic molecules
themselves.
2.2.1 Use of Living Production
Systems
Unlike the use of nonliving chemical reagents in
the synthetic manufacture of chemical drugs, living
systems (whether bacteria, yeast, animal or
human cells; viruses; transgenic animals or
plants) are used in the production of biologics.
Unlike the use of harsh environments to carry out
the synthesis of chemical drugs (e.g., organic solvents,
high temperatures and pressures), biologic
production is carried out under aqueous controlled-temperature
conditions that must be protected
from ongoing risk of contamination by
other living microorganisms in the environment.
For living systems to produce a biologic, the living
system must be kept alive, must be happy,
and must be healthy:
Living systems must be kept alive. Around the•
clock, 24/7, for as long as needed to produce
the biologic. Dead cells do not produce biologics.
In the frozen state of a stored cell bank,
the dormant cells must retain their viability
upon thawing. During the cell culturing
process, maintaining an adequate amount of
viable cells is a critical quality attribute affecting
not only the total amount of biologic produced
but also the amount of process-related
impurities present (i.e., dead cells lyse releasing
their host-related impurities into the
medium). Lower product yield coupled with
higher impurity levels can challenge the
purification process capability.
Living systems must be kept happy. The man-•
ufacturing process must be appropriately controlled
to provide adequate nutrients and a
friendly environment of an appropriate oxygen
and carbon dioxide gas concentrations,
pH, and temperature. These process parameters
can impact several cellular functions and
properties such as cell metabolism, protein
glycosylation, and protein synthesis. Biologic
manufacturers go to great care and expense
into designing their biologic production process
to ensure that the cells are maximized for
overproduction of the desired biologic.
Living systems must be kept healthy. An•
adventitious agent is defined as a microorgan-
252.2 Three Major Differences of Biologics
ism—including bacteria, fungi, mycoplasma/
spiroplasma, mycobacteria, rickettsia, viruses,
protozoa, parasites, and TSE agent—that is
inadvertently introduced into the production
of a biological product. Once it contaminates
a living production system, the biologic
process and product have a serious problem. It
is a nasty world outside of the sterile environment
of a bioreactor, and multiple barriers
must be erected around the control of the manufacturing
process to protect the living system
from these adventitious agents during the production
of the biologic.
Since life generates life, it is also important to
know the heritage of the living system being
used in biologic production. Cells, due to past
exposures to viruses, may have a latent virus
infection which may be transmitted vertically
from one cell generation to the next, since the
viral genome persists within the cell. Upon stress
of the living production system (such as due to
cell aging and nutrient depletion), a latent viral
contaminant can be shocked into activity, producing
infectious particles [11]. An illustration
of a latent virus concern in a living system is
children exposed to chickenpox virus. After suffering
1–2 weeks of misery, children recover
from the initial virus infection. After the initial
attack of chickenpox, however, the chickenpox
virus lies dormant in certain nerves in the body.
For reasons that are not fully understood, the
chickenpox virus can reappear in the form of
shingles, more commonly in people with weakened
immune systems and with aging. Shingles
is characterized by a rash of blisters, which generally
develop in a band on one side of the body
and can cause severe pain that may last for weeks
and, in some people, for months or years after
the episode.
2.2.2 Impact of Manufacturing
Process on the Product
For chemical drugs, the manufacturing process
can frequently be uncoupled from the product,
which is the basis for the generics chemical drug
industry. But this is not so for biologics.
Molecular conformation, the three-dimensional
(3D) structure of the biologic, results from
folding of the molecule due to many complex
interactions: amide bonding (i.e., covalent bonding
forming the amide amino acid linkages in the
protein chain), disulfide bonding (i.e., covalent
bonding between sulfur atoms of the cysteine
amino acids), hydrogen bonding (i.e., joining
hydrogen atoms with close oxygen atoms), and
nonbonded interactions (i.e., hydrophobic and
van der Waals interactions). Molecular conformation
of biologics can be readily impacted by
subtle changes in the environment (some proteins
are only marginally stable, impacted by even
~10 kcal/mol energy shifts). Environmental
events such as temperature increases (e.g., holding
a biologic solution at room temperature versus
refrigeration), sheer forces (e.g., strong
agitation of liquid solutions), and even exposure
to light can impart enough energy into a solution
to cause a molecular conformation shift. Although
some tests methods (such as X-ray crystallography)
are available to analyze molecular conformation,
such methods are not applied routinely to
biologics. Without this analysis, it is most difficult
for a manufacturer to know if the biologic molecular
conformation has been impacted by the manufacturing
process, and if impacted, whether it
has returned to its original 3D state.
Subtle manufacturing process changes can
also have major impact on the biologic produced.
For example, although nutrient-deficient culture
media are used as a selection mechanism in certain
cases, culture media deficient in certain
amino acids may cause substitutions in the protein
produced. When recombinant E. coli cells
are starved of methionine and/or leucine while
growing, the organism will synthesize norleucine
and incorporate it in the amino acid position normally
occupied by methionine, yielding an analogue
of the wild-type protein. The presence of
these closely related products will be difficult to
separate chromatographically [12]. As another
example, the recombinant Chinese hamster ovary
(CHO) cells used to manufacture the monoclonal
antibody Rituxan (rituximab) produce a biopharmaceutical
that has varying levels of galactose at
the termini of the carbohydrate chains attached to
26 2 Biologics Are Not Chemical Drugs
the protein molecule. A small molar shift in the
number of galactose molecules on the protein
molecule profoundly impacts the biological
potency of the produced molecule, resulting in
either a reduction in potency to 80 % (when there
are 0 mol galactose/mole of protein) or an
increase in potency to 150 % (when there are
2 mol galactose/mole of protein) [13]. Carefully
controlling a complex manufacturing process to
control the amount of specific carbohydrate moieties
attached to the protein can be a major challenge
facing biologic manufacturers.
2.2.3 Complexity of the Produced
Biologic
Looking at a recombinant DNA-derived protein
or a monoclonal antibody, the complexity of the
biologic molecule is due to (1) the possible
modifications to amino acids on the intact protein,
(2) the varying carbohydrate moieties
attached to the protein, and (3) the possible
higher-order molecular structures (i.e., conformational
changes).
The DNA central theorem states that the DNA
sequence should translate directly into the final pro-
teinsequence;however,modificationstothedesired
protein can occur on both the N-terminus and the
C-terminus ends of the protein (e.g., truncation of
aminoacids).Theamidepeptidebondscanundergo
hydrolysis. Amino acids are not “rock solid”; they
can also undergo changes such as oxidation of
methionine, disulfide scrambling of cysteine, and
deamidation of glutamine and asparagine.
Glycan moieties (i.e., the carbohydrate moieties)
attached to different sites on the protein
present considerable heterogeneity: different
types of monosaccharides present and linked in
different sequences, length, and branching of carbohydrate
chains, etc.
Taken together, if one assumes that all possible
variations to the amino acids and to the glycan
moieties can occur, it has been estimated that
approximately 100 million possible molecular
variants of a monoclonal antibody molecule
could occur [14]. And these possible molecular
variants cannot be taken lightly, since there are
potential clinical safety concerns associated with
them [15]:
Biotechnology-derived analogs to human endogenous
proteins may trigger an immune response
due to variations in the amino acid sequence or
changes to the protein structure as a result of
posttranslational modifications, physical, chemical
or enzymatic degradation and/or modification e.g.
deamidation, oxidation and sulfatation during all
steps of the manufacturing process and during storage.
Fusion proteins composed of a foreign and
self-protein are of particular concern because of
the potential of the foreign moiety to provoke an
immune response to the self-protein (epitopespreading).
Identification of the antigenic moiety
of the fusion protein is advisable. Glycosylation is
a frequent posttranslational modification of biotechnology-derived
therapeutic proteins. These
modifications may differ in the number and position
of glycosylation sites as well as sequence,
chain length and branching of the attached
oligosaccharide.
The size of the biologic molecule along with
the close similarity with other similar proteins
increases the challenge for Quality Control (QC)
to develop appropriate test methods for analysis
of these products. Take, for example, the need of
a specific fingerprint identification test. For a
chemical drug, infrared (IR) spectral analysis is a
suitable fingerprint identification test. The test is
specific, identifying functional groups on the
molecule, and appropriate for many chemical
drugs. According to the United States
Pharmacopeia (USP) <197> Spectrophotometric
Identification Tests: “the IR absorption spectrum
of a substance, compared with that obtained concomitantly
for the corresponding USP Reference
Standard, provides perhaps the most conclusive
evidence of the identity of the substance that can
be realized from any single test” [16]. Such an IR
fingerprint identity test, performed under current
good manufacturing practice (cGMP), takes less
than a half a day to complete for a chemical drug.
However, for a biologic protein or monoclonal
antibody, the IR fingerprint identity test is not
effective; instead, a peptide mapping fingerprint
identification test is necessary. According to USP
<1047> Biotechnology-Derived Articles—Tests,
Peptide Mapping: “peptide mapping is an identity
test for proteins … it is a powerful test that is
capable of identifying single amino acid changes
272.3 Biosimilar, Not “Biogeneric”
resulting from events such as errors in the reading
of complementary DNA (cDNA) sequences or
point mutations” [17]. A peptide mapping
fingerprint identity test, performed under current
good manufacturing practice (cGMP), takes
from several days to up to a week to complete for
a biologic protein (e.g., Insulin Human USP
peptide mapping identity test requires a 6-h enzymatic
incubation followed by a 90-min chromatographic
gradient program for each sample to be
tested [18]).
The enhanced sophistication in the testing
required by QC for a biologic, across many of the
tests that must be performed (e.g., biological
functioning potency assays and residual host cell
process impurity tests), explains why QC resource
is much more intensive for biologics than for
chemical drugs.
2.3 Biosimilar, Not “Biogeneric”
A chemical drug can be approved as a generic
drug product. However, a biosimilar biological
product (also referred to as subsequent entry biologics
or similar biotherapeutic product) is best
viewed as a similar biologic and not as a generic.
A generic chemical drug product is one that is
comparable to an innovator drug product in dosage
form, strength, route of administration, quality,
performance characteristics, and intended
use. Generic drug applications are termed “abbreviated”
because they are generally not required to
include preclinical (animal) and clinical (human)
data to establish safety and effectiveness. Instead,
generic applicants must scientifically demonstrate
that their product is bioequivalent (i.e., performs
in the same manner as the innovator drug).
One way scientists demonstrate bioequivalence is
to measure the time it takes the generic drug to
reach the bloodstream in 24–36 healthy, volunteers.
This gives them the rate of absorption, or
bioavailability, of the generic drug, which they
can then compare to that of the innovator drug.
The generic version must deliver the same amount
of active ingredients into a patient’s bloodstream
in the same amount of time as the innovator drug.
A chemical drug generic application expedites
the availability of less costly drugs because the
regulatory authority can approve an application
to market a generic version of a brand-name reference
listed drug (RLD) without conducting
costly and duplicative clinical trials. Both the
U.S. FDA [19] and EMA [20] approve generic
chemical drugs for market release.
A similar biologic is not pharmaceutically
equivalent to a brand-name reference listed drug
(RLD). A similar biologic is not a generic, as
clearly stated by the regulatory authorities:
EMA [21]
It should be recognised that, by definition, similar
biological medicinal products are not generic
medicinal products, since it could be expected that
there may be subtle differences between similar
biological medicinal products from different manufacturers
or compared with reference products,
which may not be fully apparent until greater experience
in their use has been established.
Health Canada [22]
The term, subsequent entry biologic, was chosen
as an alternative to “biogeneric” or “generic biologic”
in order to clearly distinguish between the
regulatory process (and product characteristics) for
SEBs and that which is currently used for generic
pharmaceutical drugs.
World Health Organization (WHO) [23]
The term ‘generic’ medicine is used to describe
chemical, small molecule medicinal products that
are structurally and therapeutically equivalent to
an originator product whose patent and/or data
protection period has expired. The demonstration
of bioequivalence of the generic medicine with a
reference product is usually appropriate and
sufficient to infer therapeutic equivalence between
the generic medicine and the reference product.
However, the approach established for generic
medicines is not suitable for development, evaluation
and licensing of SBPs since biotherapeutics
consist of relatively large, and complex proteins
that are difficult to characterize.
A similar biologic relies not just on CMC
comparability but also on nonclinical and clinical
comparability generated by the manufacturer.
2.3.1 EMA: Biosimilar Medicines
The EMA has a matured pathway for similar biologics,
having released the first guidelines in
2005. In principle, the concept of similar biolog-
28 2 Biologics Are Not Chemical Drugs
ics could be applicable to any biologic; however,
in practice, the success of such an approach
depends upon the ability to thoroughly characterize
the molecule and demonstrate the similar
nature to the reference listed drug. Thus, the
EMA currently limits biosimilars to highly
purified products, such as the biotechnologyderived
medicinal products.
At present, the following biologics are listed
by EMA as too difficult to thoroughly characterize
and to be considered for biosimilars [24]:
Biological substances arising from extraction•
from biological sources
Vaccines•
Plasma-derived proteins (and their recombi-•
nant alternatives)
Gene and cellular therapy products•
For approval as a biosimilar, (1) full CMC
information must be provided in a MAA submission,
(2) an acceptable reference listed drug
must be used as the comparator, and (3) extensive
state-of-the-art characterization studies
must be applied to the similar biological and
reference medicinal products in parallel at both
the active substance and the medicinal product
levels to demonstrate with a high level of assurance
that the quality of the similar biological
medicinal product is comparable to the reference
medicinal product. The quality of the biosimilar
does not have to be identical to the
reference listed drug, but it must be highly similar,
and any differences identified need to be
justified [25].
But, also most importantly, for approval as a
biosimilar, both nonclinical and clinical comparability
studies must be considered [26]:
The Marketing Authorisation (MA) application
dossier of a biological medicinal product claimed
to be similar to a reference medicinal product
already authorised shall provide a full quality dossier.
Comparable clinical efficacy and safety has to
be demonstrated.
The EMA has published a number of productspecific
biosimilar guidances that provide
case-by-case recommendations for these nonclinical
and clinical comparability studies (see
Table 2.1).
2.3.2 Health Canada: Subsequent
Entry Biologics
A subsequent entry biologic (SEB) is a biologic
drug that enters the market subsequent to a version
previously authorized in Canada and with
demonstrated similarity to a reference biologic
drug. A subsequent entry biologic relies in part
on prior information regarding safety and efficacy
that is deemed relevant due to the demonstration
of similarity to the reference biologic drug and
which influences the amount and type of original
data required.
Submission requirements for SEBs are determined
on a case-by-case basis by Health Canada.
These requirements include the following [27]:
A complete chemistry and manufacturing data•
package for the SEB
A rationale for the choice of the innovator bio-•
logic as the comparator and extensive published
information on its safety and efficacy
Sufficient characterization information to dem-•
onstrate both chemical and biological comparability
of the SEB to the innovator product
chosen as the comparator
Sufficient comparative animal toxicity and•
toxicological data, where appropriate
Pharmacodynamic data to demonstrate compara-•
ble bioactivity based on parameters or surrogate
markers that are clinically relevant and validated
Pharmacokinetic data to demonstrate compa-•
rable bioavailability of the SEB to the innovator
product based on suitable validated
pharmacokinetic parameters
Table 2.1 EMA nonclinical/clinical biosimilarity guidelines
(Information obtained from the EMA Human
Medicines Multidisciplinary: Biosimilar website; www.
ema.europa.eu/ema/index.jsp?curl=pages/regulation/
general/general_content_000408.jsp&murl=menus/regu-
lations/regulations.jsp&mid=WC0b01ac058002958c)
Product type
Recombinant granulocyte-colony-stimulating factor
(2006)
Somatropin (recombinant human growth hormone) (2006)
Recombinant interferon-alpha (2009)
Recombinant erythropoietins (2010)
Recombinant follicle stimulation hormone (2013)
Recombinant interferon-beta (2013)
Recombinant human insulin and insulin analogs (2012)
Monoclonal antibodies (2012)
292.3 Biosimilar, Not “Biogeneric”
Data characterizing the immunogenic profile of•
the SEB in humans and its potential impact on
safety and efficacy
A clinical package which demonstrates the•
safety and efficacy of the SEB including
comparative studies between the SEB and
innovator products, and data for the innovator
product in the public domain
A final determination of similarity is based on
a combination of analytical testing, biological
assays, and nonclinical and clinical comparability
data. However, to be considered a SEB by
Health Canada, the weight of evidence needs to
be provided by the CMC comparability.
2.3.3 WHO: Similar Biotherapeutic
Products
The WHO guidelines cover ROW (rest-of-theworld)
countries, or have been stated MOW
(most-of-the-world) countries, and as such provide
important guidance to many national competent
authorities (NCAs). The WHO employs
the term “similar biotherapeutic product” (SBP)
for a biotherapeutic product which is similar in
terms of quality, safety, and efficacy to an already
licensed reference biotherapeutic product.
Decision making by the NCAs regarding the
licensing of SBPs is based on scientific evidence.
The onus is on the manufacturer to provide the
necessary evidence to support the application for
licensing.
Atpresent,thefollowingbiologicsareexcluded
by the WHO for consideration as an SBP:
Vaccines•
Plasma-derived proteins (and their recombi-•
nant alternatives)
The CMC comparison showing molecular and
biological functional similarity between the SBP
and the RBP (Reference Biotherapeutic Product)
is indispensable. But it is the totality of CMC and
nonclinical and clinical comparability data that
will determine if the SBP can ultimately be
approved [28]:
In addition to the quality data, SBPs require nonclinical
and clinical data generated with the product
itself. The amount of non-clinical and clinical
data considered necessary will depend on the product
or class of products, the extent of characterization
possible undertaken using state-of-the-art
analytical methods, on observed or potential differences
between the SBP and the RBP, and on the
clinical experience with the product class (e.g.
safety/immunogenicity concerns in a specific indication).
A case by case approach is clearly needed
for each class of products.
2.3.4 FDA: Follow-On Protein Products
The FD&C Act permits the FDA to approve biological
products regulated under this law using
the 505(b)(2) abbreviated NDA pathway (see
Table 2.2).
Janet Woodcock, Deputy Commission of
the FDA, in 2007, presented the following
summary of how the FDA uses this 505(b)(2)
NDA abbreviated pathway for “follow-on
proteins” (FOPs) [29]:
Even though protein products are more complex
than small molecules, FDA has applied its expertise
and experience to approve certain follow-on
protein products in applications described in section
505(b)(2) of the FDC Act. Some examples of
products approved in this manner are: Hylenex
(hyaluronidase recombinant human), Hydase
Table 2.2 Three regulatory approval pathways within
the FD&C Act
505(b)(1) NDA
pathway
Standard approval mechanism for new
drugs—full CMC, safety and efficacy
studies, new drug stands on the merits
of its own data
505(b)(2) NDA
pathway
This in an abbreviated approval
mechanism that permits an applicant
to rely on published literature or on
the agency’s finding of safety and
effectiveness for a referenced
approved drug product to support
approval of a proposed product. The
applicant must demonstrate that
reliance on the previous finding of
safety and effectiveness is
scientifically justified and must submit
whatever additional nonclinical and
clinical data are necessary to establish
that the proposed product is safe and
effective
505(j) ANDA
pathway
This is the abbreviated approval
mechanism for duplicates of drugs
already approved under section 505 of
the Act—chemical generics
30 2 Biologics Are Not Chemical Drugs
(hyaluronidase), Fortical (calcitonin salmon
recombinant) Nasal Spray, Amphadase
(hyaluronidase), GlucaGen (glucagon recombinant
for injection), and Omnitrope (somatropin
[rDNA origin]).
Omnitrope is a human growth hormone product
derived from recombinant DNA processes.
Human growth hormone is a single-chain, 191
amino acid, nonglycosylated protein. Its amino
acid sequence is well known and physicochemical
tests are able to determine the complex folded
structure of human growth hormone products.
There are also clinically relevant bioassays and
validated biomarkers (laboratory indicators of
effect) available to assess the performance of
human growth hormone products. Human growth
hormone has a long and well-documented clinical
history as replacement therapy for growth failure
in pediatric patients due to endogenous growth
hormone deficiency, and its mechanism of action
and toxicity profile are well established. Some
marketed human growth hormone products are
approved for other uses, such as therapy for growth
failure associated with chronic renal insufficiency
and replacement of endogenous growth hormone
in adults with growth hormone deficiency. The
original marketed versions of human growth hormone
were derived from the pituitary glands of
human cadavers. The first recombinant version
was approved in 1985. Since then, several more
recombinant human growth hormone products
have been approved under section 505(b)(1) of the
FDC Act (i.e., each product approval relied on
original clinical data developed specifically for
that product, not an abbreviated pathway).
Omnitrope is the first recombinant human
growth hormone product approved through the
abbreviated pathway described by section 505(b)
(2) of the FDC Act. It was approved for (1) longterm
treatment of pediatric patients who have
growth failure due to inadequate secretion of
endogenous growth hormone and (2) long-term
replacement therapy in adults with growth hormone
deficiency (either childhood or adult onset).
The approval of Omnitrope was based on new data
specific to Omnitrope (but less new data than
would be needed to support an approval under section
505(b)(1)) and also relied on the approval of
Genotropin (a previously approved version of
rDNA-derived somatropin) for the same indications
proposed. Specifically, the approval was
based on the following:
Physicochemical testing that established,•
among other things, that the structure of the
active ingredient in Omnitrope is highly similar
to the structure of the active ingredient in
Genotropin;
New non-clinical pharmacology and toxicol-•
ogy data specific to Omnitrope;
Vast clinical experience and a wealth of pub-•
lished literature concerning the clinical effects
(safety and effectiveness) of human growth
hormone;
Pharmacokinetic, pharmacodynamic, and com-•
parative bioavailability data that established,
among other things, that Omnitrope and
Genotropin are highly similar based on pharmacokinetic
parameters and pharmacodynamic
responses;
Clinical efficacy and safety data from con-•
trolled trials comparing Omnitrope to
Genotropin and from long-term trials with
Omnitrope in pediatric patients; and
FDA’s conclusions that Genotropin is safe•
and effective for the indications for which
approval was sought in the Omnitrope application
and that Omnitrope is highly similar to
Genotropin.
Omnitrope has not been rated by FDA as therapeutically
equivalent (that is, substitutable) to any
other approved human growth hormone product.
2.3.5 FDA: Biosimilar Biological
Products
Modification of the PHS Act by the Biologics
Price Competition and Innovation (BPCI) Act of
2009 finally permits the FDA to approve biopharmaceuticals
and biologics regulated under this
law using an abbreviated BLA pathway (see
Table 2.3).
FDA employs the term “biosimilar biological
product” for a biological product which is similar
in terms of quality, safety, and efficacy to an
already PHS Act-licensed reference biological
product. At present, only the therapeutic protein
biologics (recombinant proteins and monoclonal
antibodies) are under consideration as possible
biosimilar biological products.
FDA also employs two terms, “biosimilarity”
and “interchangeability” [30]:
Biosimilarity to mean that the biological product is
highly similar to the reference product notwithstanding
minor differences in clinically inactive
components and that ‘there are no clinically meaningful
differences between the biological product
and the reference product in terms of the safety,
purity, and potency of the product
To meet the higher standard of ‘interchangeability’,
an applicant must provide sufficient information
to demonstrate biosimilarity, and also to
demonstrate that the biological product can be
expected to produce the same clinical result as the
reference product in any given patient and, if the
biological product is administered more than once
312.4 Never Say Never
to an individual, the risk in terms of safety or
diminished efficacy of alternating or switching
between the use of the biological product and the
reference product is not greater than the risk of
using the reference product without such alternation
or switch
The CMC comparison showing molecular and
biological functional similarity between the biosimilar
biological product and the reference bio-
logicalproductisindispensable.Butitisthetotality
of CMC and nonclinical and clinical comparability
data that will determine if the biosimilar biological
product can ultimately be approved [31]:
In evaluating a sponsor’s demonstration of biosimilarity,
FDA will consider the totality of the data
and information submitted in the application,
including structural and functional characterization,
nonclinical evaluation, human PK and PD
data, clinical immunogenicity data, and clinical
safety and effectiveness data. FDA intends to use a
risk-based, totality-of-the-evidence approach to
evaluate all available data and information submitted
in support of the biosimilarity of the proposed
product.
2.4 Never Say Never
When I entered the biologic industry 35 years
ago, the dogma of the regulatory authorities
was as follows: “the biologic process defines the
biologic product.” Unlike chemical drugs which
had a risk-based assessment for allowing
manufacturing process changes, biologics at that
time had a fixed high risk which required regulatory
authority preapproval for almost all manufacturing
process changes. Then, between the
1980s and 1990s, the regulatory authorities had
the opportunity to review numerous recombinant
DNA-derived protein and monoclonal antibody
biologics for market approval. This helped shape
their current regulatory authority dogma which is
as follows: “the biologic process may impact the
biologic product.” Today, a biologic manufacturing
process change is now also based on a riskbased
assessment review. And it is now the
responsibility of the biologic manufacturer to
demonstrate to the regulatory authority what
impact, if any, a manufacturing process change
might have on the biologic product.
Might the future dogma of the regulatory
authorities be the following: “the biologic process
can be separated from the produced biologic
product?” Currently, no regulatory authority
accepts biologics as generics (i.e., completely
uncoupling the manufacturing process from the
biologic produced). But who knows what changes
in regulatory authority dogma the future holds.
Already, EMA has raised this discussion point in
a concept paper [32]:
Discussion is needed to clarify if in exceptional
situations, e.g. where a very simple biological fully
characterised on the quality level, a biological
medicinal product could be authorised based on a
bioequivalence study only combined with an
extensive quality comparability exercise.
Table 2.3 Two regulatory approval pathways within the PHS Act
BLA pathway 351(a) Standard approval mechanism for new biologics—full CMC, safety and efficacy studies,
new biologic stands on the merits of its own data
Abbreviated BLA
pathway 351(k)
A sponsor may seek approval of a “biosimilar” product under new section 351(k) of the
PHS Act
A biological product may be demonstrated to be “biosimilar” if data show that the
product is “highly similar” to the reference product notwithstanding minor differences in
clinically inactive components and there are no clinically meaningful differences between
the biological product and the reference product in terms of safety, purity, and potency
In order to meet the higher standard of interchangeability, a sponsor must demonstrate
that the biosimilar product can be expected to produce the same clinical result as the
reference product in any given patient and, for a biological product that is administered
more than once, that the risk of alternating or switching between use of the biosimilar
product and the reference product is not greater than the risk of maintaining the patient on
the reference product. Interchangeable products may be substituted for the reference
product by a pharmacist without the intervention of the prescribing health-care provider
32 2 Biologics Are Not Chemical Drugs
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http://www.springer.com/978-1-4614-6915-5