FOCUS  ON...

BIOSIMILARS

Opportunities and Challenges

in Biosimilar Development

LY
Pankaj S. Chaudhari, Rajalaxmi Nath, and Sanjeev K. Gupta

N
A
biosimilar biotherapeutic Regulatory Framework

O
product is similar (but not of Biosimilars
identical) in terms of quality, Table 4 presents biosimilar regulatory

N
safety, and efficacy to an pathways for Europe and the United
already licensed reference product. States. The European Union (EU)
Unlike generic small molecules, it is pioneered development of regulatory

IO
difficult to standardize such inherently requirements for biosimilars in 2005.
complex products based on complicated The EMA also was the first regulatory

S
manufacturing processes. Table 1 agency to authorize biosimilars for
describes the main differences between STOCK.ADOBE.COM
market. Europe’s extensive experience

biosimilar and generic drug molecules.
The global biosimilar market is
growing rapidly as patents on
blockbuster biologic drugs expire
(Table 2) and other healthcare sectors
focus on reduction of costs. Biologics
are among the highest-cost treatments
IS
gained with licensed biosimilars has led
have on patients in terms of safety and to robust regulatory processing by the
efficacy. EMA, with a recent guideline revision
M
Developing and manufacturing adopted by the Committee for Human
biosimilars is challenging, so well- Medicinal Products (CHMP) on
R
established biopharmaceutical October 2014. In 2015, the first US
companies are investing in these biosimilar — Zarxio (filgrastim) from
E

on the global market today, which important medicines. As Table 3 shows, Sandoz — encouraged development of
implies the need for low-cost Europe is leading the way. The United biosimilars for that country as well.
P

alternatives. In emerging markets, States approved its fourth biosimilar in The US Food and Drug
biosimilars already offer more September 2016, compared with 15 Administration (FDA) released its final
affordable prices, which are not only products — marketed under 26 distinct biosimilar guideline on 28 April 2015.
H

attractive, but indispensable to brands — already approved by the Biosimilar Nomenclature: The
economies where expensive treatments European Medicines Agency (2, 3). The complex nature of biological
IT

are not financially feasible (1). market will continue to grow as best- molecules requires specific
Interchangeability of biosimilars could selling biologics come off patent in nomenclature guidelines. Naming
W

have a big impact on drug budgets coming years (4). Hundreds of biosimilars has further increased this
around the world. However, concerns companies worldwide are developing complexity, and to date, several
remain about the effect that could biosimilars to target diverse markets. different and inconsistent conventions
T

have been applied around the world

Table 1:  Major difference between biosimilars and generic drugs
(6). Often, biosimilar and reference
IN

products may share the same name.

Characteristics Biosimilars Generic Chemical Drugs
Together with naming
Chemical Complex, heterogeneous, with differences Simple, well defined, and
inconsistencies, that has led to
R

structure in protein folding and glycosylation chemically identical to a

reference product concern over the strength of the
Analytical Almost impossible to fully characterize; Ensures that active drug in a World Health Organization’s
P

characterization similar but not identical to reference generic product is identical to International Nonproprietary Name
products that of the reference product
(INN) system currently in place.
E

Manufacturing Very complex; produced in living cells, Relatively simple, uses organic
process with several stages of purification and medicinal chemistry reactions
The FDA defined how biologicals
R

production should be named in a January 2017

Impact of a Small changes in manufacturing process Likely to be negligible guidance (7), which states that each
process change can alter final protein structure and because the end products are biosimilar must have a proper name
function identical
made up of a core name hyphenated to
Development $100–200 million/molecule $3–5 million/molecule
cost
a four-letter suffix representing the
Immunogenicity Immunogenic Mostly nonimmunogenic
developer. For example, Adalimumab-

24 BioProcess International 15(5) M ay 2017

atto (Amjevita) is a biosimilar of 1) can vary in their primary amino First, the DNA sequence that
AbbVie’s Humira drug. acid sequence or through encodes a desired biosimilar is
Those FDA-designated suffixes modifications made to their amino identified, isolated, inserted into a
should prevent inadvertent substitution acid chains (e.g., glycosylation, vector, and incorporated into the
of products. The agency states that PEGylation, or addition of other side genome of a suitable host cell (e.g.,
these products thus will be chains to form a secondary structure) bacterium or mammalian cell).
distinguishable so that only products and in their higher-order structure Bacterial host cells are inexpensive
that have been approved as (e.g., folding to form a tertiary and easy to grow, and they generate
interchangeable biologicals (biosimilars) structure, more complex interactions high product yields. But they cannot
for a particular indication will replace to form a quaternary structure). produce large, complex proteins such
innovator treatments for that indication. Proprietary biomanufacturing as MAbs. By contrast, mammalian
This is intended to prevent accidental processes and environmental cells do so, but they are more sensitive
alternation between different biological conditions used in development of and costly, and they generate relatively
products that share the same core name. innovator products usually are difficult low product yields. A master cell bank
Biosimilars are receiving approval for biosimilar manufacturers to with identical cells that produce a
in Europe before receiving it in the replicate. So biosimilars are highly desired protein is established through
United States. However, no naming unlikely to be completely identical to cell screening and selection. That
convention has been established in comparator products. bank is used to culture additional cells
Europe to date. There, biosimilars
share the same INN with innovator
products, which can create confusion Table 3a:  Biosimilars approved on the European market (5); * CHMP positive opinion
among healthcare professionals. INN Names Brand Names Company Names Approvals
Filgrastim Accofil, Biograstim, Accord Healthcare, CT 18 Sep 2014, 15 Sep
Biosimilar Development Filgrastim Hexal, Arzneimittel, Hexal, 2008, 06 Feb 2009, 18
Grastofil Apotex, Hospira, Oct 2013, 08 Jun 2010,
and Manufacturing Nivestim, Ratiograstim Ratiopharm, Teva 15 Sep 2008, 15 Sep
Therapeutic proteins derived through Tevagrastim, Zarzio Generics, Sandoz 2008, 06 Feb 2009
recombinant DNA technology (Figure Adalimumab Amgevita, Solymbic Amgen 26 Jan 2017*, 26 Jan
2017*
Etanercept Benepali Samsung Bioepis 14 Jan 2016
Table 2:  Patent status of some innovator Infliximab Remsima, Flixabi, Celltrion, Samsung 10 Sep 2013, 26 May
biologics (3) Inflectra Bioepis, Hospira 2016, 10 Sep 2013
Exclusivity Rituximab Truxima Celltrion 15 Dec 2016*
Reference Expiration
INN Name Product EU USA Epoetin zeta Retacrit, Silapo Hospira, STADA R&D 18 Dec 2007, 18 Dec
2007
Adalimumab Humaria 2018 2016
Epoetin alfa Binocrit, Abseamed, Sandoz, Medice 28 Aug 2007, 28 Aug
Etanercept Enbrel 2015 2028 Epoetin alfa Arzneimittel, Hexal 2007, 28 Aug 2007
Infliximab Remicade 2015 2018 Follitropin alfa Ovaleap Teva Pharma 27 Sep 2013
Rituximab Mabthera 2013 2018 Somatropin Omnitrope Sandoz 12 April 2006
Bevacizumab Avastin 2022 2019 Insulin Abasaglar, Lusduna Eli Lilly/Boehringer 9 Sep 2014, 4 Jan 2017
Trastuzumab Herceptin 2014 2019 Ingelheim, Merck (MSD)
Pegfilgrastim Neulasta 2017 2015 Enoxaparin sodium Inhixa Techdow Europe 15 Sep 2016
Ranibizumab Lucentis 2022 2020 Teriparatide Movymia STADA Arzneimitte 10 Nov 2016*

Figure 1:  Biosimilar production: source of variation between manufacturers (24)

Cloning, Protein Expression, and Production

Cloning of specific Recombinant Transfer into Cell Protein production

gene into DNA vector DNA Plasmid host cell expansion in bioreactor

Same gene sequence Different vector Different Different Different bioreactor

expression cell line conditions

Protein Purification and Formulation

Protein recovery Protein Purified Protein Formulation

through filtration purification by bulk characterization
and centrifugation chromatography and stability

Different operating Different binding and Different Different methods, Different

conditions elution conditions filter reagents, and suppliers of
supplier reference standards excipients

26 BioProcess International 15(5) M ay 2017

 Table 3b:  Biosimilars approved on the US market (5)
at increasing scale under strictly
INN Name Brand Name Company Name Approval Date
defined conditions that optimize
Adalimumab Amjevita Amgen 23 Sept 2016
protein production.
Insulin glargine Basaglar Eli Lilly and Boehringer Ingelheim 16 Dec 2015
In downstream processing,
Etanercept Erelzi Sandoz 30 Aug 2016
undesired proteins and other impurities
Infliximab Inflectra Pfizer (Hospira) 5 Apr 2016
are removed from culture supernatant.
Filgrastim Zarxio Sandoz 6 Mar 2015
Harvested protein is analyzed for
uniformity in its three-dimensional
Figure 2:  Reference standard requirements for biosimilar development in major markets
structure and potency using a number
of analytical methods, including EU reference product EU approval
physicochemical and biological tests.
Finally, the purified drug substance is CMC
In vitro nonclinical
formulated with added excipients (e.g.,
In vivo nonclinical CMC bridging
antioxidants, osmotic agents, and (repeat-dose toxicity,
US
USA
reference PK/PD bridging
buffers), filled into containers and immunotoxicity) product approval
Pediatric studies
external packaging, then stored and Phase 1 PK/PD
shipped under appropriate Efficacy,
environmental conditions. immunogenicity
Biosimilar use of different
CMC = chemistry, manufacturing, and controls; PK = pharmacokinetics; PD = pharmacodynamics
expression systems from those
producing reference drugs can change
a protein’s posttranslational systems for cell screening and the effects of such changes using
modifications (e.g., glycosylation selection to establish the master cell appropriate analytical methods,
profile), which in turn can affect bank, culture media, methods for functional assays, and animal and
product safety or effectiveness (8). production or purification, and clinical studies to ensure that such
Modification of any steps in excipients) can alter the effectiveness changes do not adversely affect the
biomanufacturing (e.g., use of a and safety of a product. Thus, identity, quality, purity, potency,
different vector to create host cells, biosimilar manufacturers must assess safety, or effectiveness of their

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Table 4:  Regulatory framework in Europe and the United States — differences between European Medicines Agency (EMA) and Food and Drug
Administration (FDA) pathways; areas of overlap are tinted.
Criteria EMA FDA
First approved biosimilar Omnitrope (somatropin), 2006 Zarxio (filgrastim-sndz), 2015
Biosimilar regulatory paradigm Demonstration that a potential biosimilar is highly similar to its reference product in safety, purity, and
potency/efficacy with no clinically meaningful differences
In vivo comparative toxicology Not required routinely, relies more on Routinely required, although the agency can waive this
studies in vitro evaluation of structure–function
relationships
Multistep comparison of a Analytical and functional studies; in vivo nonclinical analyses; clinical pharmacokinetic/pharmacodynamic
biosimilar to its reference assessments; head-to-head clinical trials in the most sensitive population(s) — safety, efficacy, and
product immunogenicity studies
Biosimilar review process Nontherapeutically aligned structure in centralized Therapeutically aligned structure with multiple levels of
CHMP reviews supervision and oversight
Legal pathway A separate branch of the generic pathway (Directive Biologics Price Competition and Innovation Act (BPCI
2001/83/EC, Article 10.4) Act) of 2009

Meetings between
developers/sponsors and
regulatory agencies
Interagency meetings
Centralized advice procedure by the EU CHMP FDA meeting structure defined by the Biosimilar User
Scientific Advice Working Party provides mostly Fee Act (BsUFA for biosimilar applications)
written advice; meetings called when regulators
disagree with a sponsor’s proposed plan
Advice procedures with individual EU country health Biosimilar product development (BPD) meetings enable
authorities, usually involving meetings Biologic License Applications under 351(k) pathway
EMA and FDA cluster meetings (closed, regulators-only meetings); EMA/FDA parallel advice (for companies)

products. That also is a question
addressed by regulatory agencies when
they evaluate biosimilars for approval.
Reference Standard Selection: The
EMA has clear guidelines on use of
reference standards for similar biological
medicinal products (9). To facilitate the
global development of biosimilars and
prevent unnecessary repetition of
clinical trials, it may be possible for an
applicant to compare its biosimilar in
certain clinical studies and in vivo
nonclinical animal studies with a
reference product that is not authorized
in the European Economic Area
(EEA), but that comparator should be
authorized by a regulatory authority
with similar scientific and regulatory
standards (e.g., signatories to the
International Council on
Harmonisation of Technical
Requirements for the Registration of
Pharmaceuticals for Human Use, ICH).
According to the EMA biosimilar
guidelines (Figure 2), if an applicant
performs parallel development for
Europe and the United States, then
inclusion of US reference standards is
necessary. Scientifically, the type of
bridging data needed always will
include data from analytical studies
(e.g., structural and functional data)
that compare all three products (the
proposed biosimilar, the EU reference
product, and the US comparator).
They may include data from clinical
pharmacokinetic (PK) and/or
pharmacodynamic (PD) bridging
studies for all three products as well.
Extensive Comparability Data:
Biological systems are inherently
variable, and expression systems can
substantially affect the structure and
function of proteins they produce. Thus,
biological products are extensively
characterized for variability, even among
different lots of the same product.
Stringent EMA and FDA regulations
require comprehensive structural and
functional analytic comparative data to
demonstrate comparability before
initiating preclinical testing and clinical
PK/PD studies (10).
Biomolecular analyses fall under
three categories: physicochemical,
immunological, and biological assays.
Table 5 summarizes those used in
comparability studies of biosimilar and
reference products. Demonstrating a
high level of analytical similarity
between those drugs is the first step.
All structural elements and
modifications of a protein should be
evaluated with full capability of
detecting differences. Based on
observed characteristics of the reference
product, a quality target product profile
(QTPP) is defined for a biosimilar.
Control Strategy: The term “control
strategy” refers to a combination of
input, procedural, and testing controls
that ensure that a bioprocess
consistently delivers products that meet
quality attribute requirements. The
level of control needed for each
individual quality attribute is
determined based on the criticality level
of that attribute and the capability of a
process to deliver product consistently
that meets quality expectations.
An integrated control strategy
includes procedural and raw-material
controls, in-process control (IPC)
tests, process monitoring and product
data monitoring, release specification
testing, stability testing, process
validation, characterization testing,
control of process validation, and
comparability testing. Figure 3
illustrates development of a control
strategy and its importance to product
lifecycle management
Establishment of specifications is a
major area of uncertainty for a biosimilar
integrated control strategy. Regulatory
expectations for commercial
specifications are not completely clear,
however. EU guidance mentions that
selection of tests to be included in
specifications (or control strategy) is
product specific for both drug substance
and drug product, and thus should be
defined as described in ICH Q6B (11).
US guidance, however, offers no specific
reference to expectations for development
of a biosimilar control strategy.
Manufacturing Changes and
Challenges: Some biosimilar

28 BioProcess International 15(5) M ay 2017

manufacturers may need to make
changes or alter their own
manufacturing processes — for
enhancement of product quality and
yield, adherence to upgraded regulatory
policies, or increased efficiency and
improved reliability of the
biomanufacturing process (12).
Modifications to any biological product
— whether originator or biosimilar —
that result from manufacturing changes
are subject to tight regulatory controls
and limits (13). Table 6 illustrates such
changes and associated regulatory
requirements during different stages of
manufacturing.
Clinical Development: Clinical trials
for biosimilars must demonstrate safety
and efficacy comparable to their
comparators through sequential PK/
PD, immunogenicity, and efficacy/
safety trials. Stand-alone phase 3
studies or combined phase 1–3 designs
without supporting PK data are
unlikely to be accepted by regulatory
reviewers. Subject to a risk-based
approach, clinical comparability
requirements vary by case. Three-arm
phase 1 clinical trials can demonstrate
comparability for a biosimilar and two
licensed versions of the same reference
product on different markets (e.g.,
Europe and the United States). That
allows developers to proceed with
pivotal phase 3 trials using a single
version of the reference product for
biosimilar approval in each respective
market (14). Extrapolation from one
indication to another is allowed by both

Figure 3:  Control strategy during biosimilar development

Preclinical Phase 1 Phase 3 Filing Launch/postlaunch

Reference product
characterization Continued
CPD P&PC PPQ process verification
Biosimilar product
and process
understanding

QBD Finalize
commercial
PQR control strategy Lifecycle
QTPP/PQ (routine testing). Management
assessment Evaluate risk of
commercial process
Raw- before process
material validation, refine Reevaluate to
assessment as appropriate. maintain and, if needed,
Identify CQA and improve control.
needs for process
control strategy.

CPD = commercial process development; QTPP = quality target product profile; P&PC = process/product characterization;
PPQ = process performance qualification; PQR = product quality risk assessment; QBD= quality by design

Table 5:  Physicochemical and biological characterization methods for comparability studies of biosimilars (8)

Characteristics Attributes Analytical Methods

Primary structure Amino acid sequence RP-HPLC, LC-ESI-MS, peptide mapping

Higher-order structure Disulfide structure, free thiol analysis, secondary and LC-ESI-MS peptide mapping, Elman assay, CD,
tertiary structure FTIR, antibody conformational array, X-ray
crystallography

Purity, charge heterogeneity, Thermal stability, monomer content, charged isoforms DSC, SEC-HPLC,SEC-MALS, SV-AUC,CE-SDS, IEF,
amino acid modification IEC-HPLC
Glycosylation Deamidation/oxidation/C-terminal variants, N-glycan LC-MS peptide mapping, LC-MS, CE-SDS, HPLC,
analysis, glycosylation, oligosaccharide profile, sialic acid HPAEC-PAD
analysis, monosaccharide content (fructose, GlcNAc,
galactose and mannose)
Potency Antigen and C1q binding, FcRn binding, antigen ELISA, SPR, cell-based neutralization assay, cell-
neutralization, apoptosis, CDC based apoptosis assay, cell-based CDC assay
FTIR: Fourier-transform infrared spectroscopy RP-HPLC = reversed-phase high-performance liquid chromatography; LC-ESI-MS = liquid chromatography with
electrospray ionization mass spectrometry; CD = circular dichroism; DSC = differential scanning calorimetry; SEC = size-exclusion chromatography; MALS =
multiangle light scattering; SV-AUC = analytical ultracentrifugation; CE-SDS = capillary electrophoresis with sodium-dodecyl sulfate; IEF = isoelectric focusing;
LC-MS = liquid chromatography with mass spectrometry; HPAEC-PAD = high-performance anion-exchange chromatography with pulsed amperometric detection;
ELISA = enzyme-linked immunosorbent assay; SPR = surface plasmon resonance; CDC = complement-dependent cytotoxicity

30 BioProcess International 15(5) M ay 2017

 the EMA and FDA for biosimilars,
although it must be supported by
strong scientific justification (15).
Interchangeability
As with generic drugs,
interchangeability would allow
biosimilars to be substituted by
pharmacists without the intervention
of a prescribing doctor. This is the
next big hurdle in the path of
biosimilars, clearing which would
create a real challenge to the reference
products’ markets (16). Such
substitution is what allows generic
medicines to gain market share rapidly
(17). However, some prescribers may
have safety concerns.
Immunogenicity studies present an
additional consideration, particularly
for interchangeable biosimilars,
although they generally are not
required for manufacturing changes.
But designation of interchangeability
would allow pharmacists to substitute
such a biosimilar for its reference like
they do with small-molecule generic
drugs (18). The candidate on which
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switching studies would be conducted
must be the same as that approved
without an interchangeability
designation. There is no higher
regulatory standard for biosimilars,
and the data burden to obtain a
designation of interchangeability is
increased (7).
To be considered interchangeable in
the United States, biosimilars must
(among other things) “be expected to
produce the same clinical result as the
reference product in any given
patient,” according to the Biologics
Price Competition and Innovation Act
of 2009. Developers also must
document that a patient could switch
back and forth between the original
and biosimilar products without
increased risk. According to the FDA’s
rules, neither biosimilars nor
interchangeable drugs can have
clinically meaningful differences in
safety when compared with the
originator products (19).
Interchangeability and substitution
of biosimilars are not within the scope
of EU regulatory approval, so there is
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no agreed-upon definition of what
interchangeability actually means to
Europe and no inclusion of such
information in the European Public
Assessment Report (EPAR) (15).
Currently, the United States is the only
country allowing for a formal such
designation among biologic products. A
recent FDA draft guideline requires
that sponsors show that a proposed
product “is biosimilar to the reference
product” (20). When a product is first
licensed as a biosimilar, that licensure
may be referenced to support the
statutory criterion for demonstrating
interchangeability on the basis of a
switching study or studies.
Opportunities and
Recommendations
Based on a literature review, we offer
in Table 7 some recommendations to
overcome barriers to the market access
for biosimilar MAbs (21). Once such
blockbusters start to go off patent in
Europe, biosimilars should become
20–30% cheaper than original MAb
products. Market competition will
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Table 6:  Manufacturing changes and regulatory recommendations
Development Stage Expected Changes Regulatory Recommendations
Early stage Change in cell line, fermentation process, raw materials used during Comparability testing generally not as
(preclinical) fermentation; order of purification steps, replacement and/or removal of extensive as for an approved product
purification steps
Late stage Change in cell line, fermentation process, raw materials used during Extensive comparability studies to confirm/
(clinical) fermentation; order of purification steps, replacement and/or removal of support that the pre- and postchange
purification steps; formulation of drug product and manufacture of drug products are not different in quality, safety,
product; new drug substance and/or new drug product and efficacy; data as per ICH Q11 (25)
After market Change in cell line, fermentation process/scale-up, raw materials; order of At this stage, product is not expected to
authorization purification steps, replacement and/or removal of purification steps; change; any changes need careful
(postapproval formulation of drug product and manufacture of drug product; new investigation and justification for safety and
changes) manufacturing site efficacy; follow variation guideline

Table 7:  Recommendations for overcoming challenges to market access

agencies. Successful development and
Barrier Recommendation commercialization of biosimilars
Manufacturing process Invest initially in advanced production processes with the help of requires business strategies that
single-use technology. Outsource technology.
integrate appropriate clinical design
Regulatory process Gain experience with regulatory process and establish alignment
between stakeholders. Engage in early dialogues with regulators.
and regulatory compliance.
Intellectual property Limit patent litigations. Eliminate evergreening benefits. Build out
Although it requires a substantial
rights further the unitary patent and unified patent litigation system. investment in time and money, the
Impossibility of Change attitude toward biosimilar switching/substitution, starting development and introduction of
substitution with physician and patient education. biosimilars ultimately should provide
Innovator’s reach Differentiate biosimilars with service offerings. Use appropriate cost savings compared with innovator
comparators in cost-effectiveness analyses.
products. The growth rate for
biosimilar MAbs might be over 25%
play a pivotal role in favor of approved the first two biosimilar by 2020. The industry of biosimilars
biosimilars. These speculations come versions of Remicade (infliximab). should bring benefits both for science
from the fact that a 30–40% price Now, those two biosimilars together and for healthcare.
reduction already has been seen for incur more sales than all the other
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DRIVING CREATIVE PROTEIN ENGINEERING & DESIGN
TO SUCCESSFULLY TRANSFORM PROMISING NEW
MOLECULES INTO DIFFERENTIATED PRODUCTS
Hear from experts in Bioconjugates and Next Generation Protein Therapeutics
Jennifer Cochran, Ph.D. Paul Carter, Ph.D.
Stanford University Genetech, Inc.
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17 Schueller T. Chances and Hurdles for
Biosimilars. CHEManager Int. 8 October 2015;
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pharma-biotech-processing/chances-and-
hurdles-biosimilars.
18 McCamish M, et al. Toward
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19 Friedman LF. An Innovation That
Could Transform the Drug Industry Faces a
Major Hurdle. Business Insider 30 April 2015;
www.businessinsider.com/biosimilars-
bioequivalence-and-interchangeability-2015-4.
20 Draft Guidance for Industry:
Considerations in Demonstrating Interchangeability
with a Reference Product. US Food and Drug
Administration: Rockville, MD, January 2017;
www.gpo.gov/fdsys/pkg/FR-2017-01-18/
pdf/2017-01042.pdf.
21 Moorkens E, et al. Overcoming Barriers
to the Market Access of Biosimilars in the
European Union: The Case Study of Biosimilar
Monoclonal Antibodies. Front. Pharmacol. 7,
2016: 193; doi:10.3389/fphar.2016.00193.
22 Rader RA. Biosimilars Pipeline
Analysis: Many Products, More Competition
Coming. BioProcess Online 26 July 2016.
23 Biosimilar Market Is Projected to be
Worth USD 32 Billion Worldwide by 2025
According to “Global Biosimilars Market, 2015–
2025.” GlobeNewswire: El Segundo, CA, 12
November 2015.
June 5-7, 2017
Paradise Point San Diego,
San Diego, CA
Catherine Coombes
HGF Limited, UK
24 A Health-System Pharmacist’s Guide to
Biosimilars: Regulatory, Scientific, and Practical
Considerations. American Society of Health-
System Pharmacists: Bethesda, MD, 2013;
http://ashpadvantagemedia.com/downloads/
biosimcentral_guidelines.pdf.
25 ICH Q11: Development and
Manufacture of Drug Substances. Federal
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p. 69634-5; www.ich.org/fileadmin/Public_
Q11/Q11_Step_4.pdf. •
Web_Site/ICH_Products/Guidelines/Quality/
Pankaj S. Chaudhari is regulatory affairs
and quality assurance (RA/QA) manager
(pankaj.chaudhari@ipca.com), Rajalaxmi
Nath is RA/QA research associate, and
corresponding author Sanjeev K. Gupta is
general manager of the advanced biotech
laboratory at Ipca Laboratories, Ltd. in
Mumbai, India; +91-22-6210-5820; sanjeev.
gupta@ipca.com; www.ipca.com.
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Keiichiro Suzuki
Salk Institute
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