“Biosimilars are generic versions of biological medicines that depend on the same mechanism of action, and are used for the same therapeutic indication, as the innovator product.

1. Pharma Bio World April 2013  27
India can Emerge as a Key Player in the
Biosimilar Segment
B
iosimilar, which are new versions
of innovator biopharmaceutical
products that are marketed after
expiration of patents, have emerged as
one of the fastest growing development
opportunities in the biopharmaceutical
sector. Regulatory agencies evaluate
biosimilars based on their level of
similarity to, rather than the exact
replication of, the innovator drug. The
need for increased analytics and the
desire for compressed timelines in
biosimilars development demands in
particular that developers must invest
early in Chemistry, Manufacturing,
and Controls (CMC) type analysis
to demonstrate comparability to the
reference molecule at every stage,
particularly during manufacturing. While
conventional generics are expected to
face competition and pricing pressures
in most developed markets, Indian
pharmaceutical companies have already
started gearing up for the next big thing —
biosimilars. These are generic versions
of biological medicines that depend on
the same mechanism of action, and are
used for the same therapeutic indication,
as the innovator product.
Recognising the opportunity, India has
already taken its first step forward to
tap the emerging opportunity in the
biosimilars’ space. While almost all
major Indian drug makers have outlined
plans, identified products and set aside
investment budgets to develop a robust
product pipeline, some have even
started rolling them into the market. For
instance, Dr Reddy’s Laboratories has
The biosimilars industry
has been growing
stupendously. In the last
few years, India has seen
a robust growth in its
biosimilars portfolio. This
article aims to identify and
analyse the biosimilars
market and the regulatory
scenario in India.
already launched a few of its significant
biosimilars in emerging markets. On
the other hand, companies like Cipla
are making huge investments in India
and outside to acquire manufacturing
facilities and potential product pipelines
in the biosimilar segment. The company
has not only acquired facilities in India
and China to develop biosimilars, more
recently, it has also rejigged some of its
investments in China to divert more funds
towards biosimilars. Similarly, Wockhardt
and Lupin have made their foray into the
niche segment.
Development Challenges
Similar biologics are developed through
sequential process to demonstrate the
similarity by extensive characterisation
studies revealing the molecular and
quality attributes with regard to the
reference biologic. Biosimilars must
be systematically engineered to match
the reference product. A comparability
exercise must be followed with the
innovator product at all levels of product
development, including: physicochemical
attributes, biological activity, preclinical in
vivo comparability, Phase I PK and safety,
and Phase III efficacy and safety.
This can be difficult because data for the
innovator product will be lacking. The
only way to get information about the
components of the innovator product is
from material that is already out in the
marketplace. Having multiple batches
of the innovator’s product, spanning a
number of years, can be extremely helpful
J Ramniwas
Founder & CEO
Sai Pharma Solutions Inc, Vadodara
“
“
Biosimilars are generic versions of biological
medicines that depend on the same mechanism
of action, and are used for the same therapeutic
indication, as the innovator product.

2. Pharma Bio World28 April 2013
during the characterisation process.
Sources of variation between manufacture
of innovator biopharmaceutical and
biosimilar are as given below:
• Use of different vector
• Different cell expression system
• Different cell line growth media and
method of expansion
• Different operating conditions
• Different binding and elution conditions
• Different methods, reagents,
reference standards
Manufacturing Process of
Biopharmaceuticals
The manufacturing process for similar
biologic should be highly consistent
and robust. If the host cell line used
for the production of reference biologic
is disclosed, it is desired to use
the same cell line as the reference
biologic. Alternatively any cell line
that is adequately characterised and
appropriate for intended use can be
used to develop a similar biologic, with
process- and product-related impurities,
the relevant immunochemical properties,
and results from accelerated degradation
studies and studies under various
stress conditions.
In order to demonstrate that you have
a similar product, you need to have
your analytical assays in place during
the process of development. These
assays will help to best replicate
what the innovator has done. Overall,
the characterisation you need to do
for a biosimilar will always be much
higher than that for a new biological
entity (NBE).
The analytical characterisation of a
biosimilar should include primary,
secondary, tertiary, and quaternary
structural assessment, biological activity,
and analysis of product and process
impurities.All of these components must be
understood and characterised during your
comparability studies of the biosimilar to
the innovator product.
appropriate justification in order to
minimise the potential for significant
changes in critical quality attributes of
the product and to avoid introduction of
certain types of process related impurities
that could impact clinical outcomes
and immunogenicity.
The data requirements for review of
manufacturing process at preclinical
submission stage include a complete
description of the manufacturing process
from development and characterisation
of cell banks, stability of clone, cell
culture/fermentation, harvest, excipients,
formulation, purification, primary
packaging interactions (if different from
reference biologic), etc.
Analytical Characterisation of Biosimilars
Thorough characterisation and
comparability exercise are required, and
details should be provided on primary and
higher-order structure, post-translational
modifications, biological activity,
Closing of
specific gene
sequence into
viral or non-viral
vector
Transfer into
host cell for
expression
Cell expansion
Protein
Production
Protein
recovery
through
filtration &
centrifugation
Protein
Purification by
chormatography
Protein
characterization
& stability
Use of different
vector
Different cell
expression
system
Different
celline growth
media &
method of
expansion
Different
operating
condition
Different
binding
& elution
conditions
Different
methods
reagents,
reference
standards
Biopharmaceutical Manufacturing
Sources of variation between manufacturing of innovator biopharmaceuticals and biosimilars
Figure 1 : Variation bitween Manufacturing of biopharmaceuticals and biosimilars

3. Pharma Bio World April 2013  29
Regulatory Issues of Concern for the
Use of Biosimilars
In order to make foray in to the global
regulated markets, Indian manufactures
will have to resolve the following issues on
the priority basis due to different sources
of variations between manufacture
of innovator biopharmaceutical and
manufacture of biosimilars:
1. Quality Issues
2. Efficacy Issues
3. Safety Issues
4. Pharmacovigilance
5. Substitution
6. Naming and Labeling
7. Regulatory Approval
Regulatory Landscape in India
Due to the complexity of biologics, a
product can only be made that is similar
to the innovator drug, not identical.
Basically, it’s impossible for two different
manufacturers to produce two identical
products even identical host expression
systems, processes, and equivalent
technologies are used. Therefore, we
have to rely on analytics to compare the
biosimilar to the innovator product on
the market.
Advances in current state-of-the-
art analytical methods enhance the
likelihood that a product will be highly
similar to another product through
better targeting of the original product’s
physicochemical and functional
properties. Sponsors with compelling
comparability data observe a reduced
regulatory burden.
The Department of Biotechnology, along
with the drug regulator (CDSCO), has
also got into action and has floated
guidelines in 2012” Guideline on similar
biologics: Regulatory Requirements
Marketing Authorisation in India “for
biosimilar drugs. The proposed norms
outline specific requirements for
pre-marketing and post-marketing data,
apart from guidelines for pre-clinical and
clinical trials for biosimilars.
The move is aimed at upgrading and
maintaining the quality of biosimilar
products that are manufactured in India. In
the development of these guidelines, the
department of biotechnology and the drug
regulator (CDSCO) have given references
of ICH guidelines so that products
developed and imported in India will be
per the global regulatory standards so that
the Indian manufactures can leverage the
technological advantage to manufacturing
quality, safe and effective products.
Regulatory applications and approvals
issued at different stages of biosimilars
product development in India are shown
in Figure 2.
Sr
No
Stage of development or
manufacturing
Regulatory
Agency involved
Application
format
Approval
format
1. Manufacturing License for test,
analysis and examination
State FDA /
CDSCO
Form 30 Form 29
2. Preclinical studies permission RCGM Form C3 Form C4
3. Submission of Preclinical study report RCGM Form C5 Form C6
4. Clinical Trial CDSCO Form 44 Permission
letter
5. Manufacturing and Marketing
permission
CDSCO Form 44 Form 46A
(Bulk
product)
Form 45/46
(Finished
product)
6 Form 46A (Bulk product)
7. Commercial Manufacturing License State FDA /
CDSCO
Form 27 D Form 28 D
8. Registration and Import License CDSCO Form 40/
Form 8
Form 41/
Form 10
traditional prescription drug, the product
must have the same active ingredient,
strength, dosage form and route of
administration as the original drug. This
means that generic drugs are the exact
same chemically as their brand name
counterparts and they act the same way
in the body.
Such a process is not possible with
biologics. Biologics manufacturers must
ensure that the manufacturing process
remains the same over time by tightly
controlling the source and nature of
starting materials and consistently
employing hundreds of process controls
that guarantee predictable results. When
The applicant should comply with the
established pharmacopoeia requirements
while testing the excipients and as well as
biological product for which monograph
is available in Indian Pharmacopoeia.
Challenge of Manufacturing Biosimilars:
For a generic drug manufacturer to
win approval of a generic version of a
a biosimilar is created, it requires a new
manufacturing process with new starting
materials. As a result, it will produce a
product that is different from and not
therapeutically equivalent with that of the
brand name biologic.
For new entrants, biosimilars
pose very different challenges to
Figure 2: Various application forms for submitting request to regulatory agencies

4. Pharma Bio World30 April 2013
Contact : jramniwas@saipharmasolutions.com
those presented by small molecule
generics, with more demanding
requirements in terms of :
• Sophisticated technologies
• Clinical development, clinical trial
expertise and proving bioequivalence
• Market access
• Manufacturingindedicatedmanufacturing
facility
• Sales and marketing capabilities
Because of the complex process of
manufacturing biologics, the only
way to establish whether there are
differences that affect the safety and
effectiveness of the biosimilars is to
conduct clinical trials on each new
product. The human body is more
sensitive than any laboratory test and
that’s why these tests are necessary
to determine if biosimilars have any
adverse impact in humans.
Advantage to Manufacturing Biosimilars
The “Guideline on similar biologics:
Regulatory Requirements Marketing
Authorisation in India” have been
developed by taking the international
regulatory standards in to consideration
so that Indian manufactures can
manufacture the biosimilars as per
global GMP regulations and can
make foray in to the world markets
like US, Europe, Japan etc with
more confidence beating all
pursuing challenges.
The Indian government has also
taken several initiatives towards
streamlining the way biosimilars/SBP
will be regulated in our country thereby
showcasing India as a key player in the
biosimilar segment.
Some of these include dissemination of
applicable guidance documents; creating
additional levels of checks (prescreening
checklist for filing, NDAC referral),
drafting of the Biotechnology Regulatory
Authority of India bill, creating public
awareness through several meetings with
stakeholders and hosting clarifications
on CDSCO site. These steps would
ensure more affordable biosimilar drugs
“
“
Generic drugs are the exact same chemically as
their brand name counterparts and they act the
same way in the body.
being manufactured and made available
to patients both in domestic and
export markets.
Conclusion:
It’s an exciting time for biosimilars. The
need of the hour is to conduct “SWOT”
analysis and strengthen our competence
and confidence by understanding the
regulatory guidelines and implementing
them as per current requirements.
As such the regulatory guidelines will
continue to evolve as we get more
experienced and biosimilars continue
hitting the market. We will also see
demand for biosimilar CMC development
continue to grow as it plays a critical role
in demonstrating comparability to the
reference product. As we are dealing with
an inherently variable system, we need to
look at biosimilars development from an
integrated standpoint. Biotechnological
medicines shall become an important
part of future healthcare landscape.
With patent expiration of innovator
products, the biosimilars will increasingly
become available. Awareness of the
deviations between biosimilars and
innovator products in terms of efficacy,
safety and immunogenicity is essential
for proper prescription and safety
of the patients.
1. Quality Issues
2. Efficacy Issues
3. Safety Issues
4. Pharmacovigilance
5. Substitution
6. Naming and Labeling
7. Regulatory Approval
Figure 3: Regulatory issues for the use of biosimilars