DEFINITION OF DRUGS UNDER DRUGSDEFINITION OF DRUGS UNDER DRUGS
AND COSMETICS ACT 1940AND COSMETICS ACT 1940
Includes all medicines ,substances, components, for internal orIncludes all medicines ,substances, components, for internal or
external use.external use.
Meant to treat, mitigate or prevent, diagnose, disease or disorderMeant to treat, mitigate or prevent, diagnose, disease or disorder
in human beings and animals.in human beings and animals.
IT INCLUDES BIOSIMILAR DRUGS (BIOLOGICS)IT INCLUDES BIOSIMILAR DRUGS (BIOLOGICS)
A standard definition of biotechnology was not reached until the
United Nations and World Health Organization accepted the 1992
Convention on Biological Diversity and defined biotechnology as:
Any technological application that uses biological systems, living
organisms or derivatives thereof, to make or modify products and
processes for specific use.
It was during the early 20th century when the term biotechnology
came into use. The term was coined in a book by Karl Ereky, a
Hungarian engineer and professor who described a technology
based on converting raw materials into a more useful product.
A drug created by means of biotechnology, especially
genetic engineering derived proteins and act as active
A pharmaceutical inherently biological in nature and
manufactured using biotechnology and it is a medicine
whose active substance is made by or derived from a living
Insulin can be produced by a living organism (such as a
bacterium or yeast), which has been given the gene that
enables it to produce insulin.
BIOPHARMACEUTICALS ……... contdBIOPHARMACEUTICALS ……... contd
Biopharmaceuticals have revolutionized the treatment of many
diseases like diabetes, malignant disorders etc., and fundamentally
different from the conventional small molecule chemical drugs.
They have very large molecules with highly complex structure which is
difficult to identify with currently available analytical methods, when
compared to simple molecular structure of chemical drugs.
Nature of the manufacturing process - in biopharmaceutical
manufacturing process defines the final product (‘process is product’)
and even a minor change in manufacturing process may lead to
The safety and efficacy profile of these biopharmaceutical products are
highly dependent on the robustness and the monitoring of quality
CLASSIFICATION OF PROTEINS
According to their biological roles
- Enzymes: Catalyses virtually all chemical reactions i.e. 6GDH
- Transport proteins i.e. Haemoglobin of erythrocytes
- Contractile or Motile proteins i.e. Actin and Myosin
- Structural proteins i.e.Collagen
- Defense proteins i.e. Immunoglobulins and Antibodies
- Regulatory proteins i.e. insulin
- Nutrient and storage proteins i.e. Ovalbumin
PEGylation is the process of covalent attachment of Poly
Ethylene Glycol (PEG) polymer chains to another molecule,
normally a drug or therapeutic protein.
PEGylation is routinely achieved by incubation of a reactive
derivative of PEG with the target molecule.
The covalent attachment of PEG to a drug or therapeutic
protein can "mask" the agent from the host's immune
system and increase the hydrodynamic size of the agent
which prolongs its circulatory time by reducing renal
PEGylation can also provide water solubility to
hydrophobic drugs and proteins.
ADVANTAGE OF PEGYLATION
PEGylation, by increasing the molecular weight of a molecule, can impart
several significant pharmacological advantages over the unmodified
form, such as:
Improved drug solubility
Reduced dosage frequency, without diminished efficacy with potentially
Extended circulating life
Increased drug stability
Enhanced protection from proteolytic degradation
PEGylated drugs have the following commercial advantages also:
Opportunities for new delivery formats and dosing regimens
Extended patent life of previously approved drugs
EIGHT PEGylated proteins have been commercialized following
1. ADAGEN (pegademase bovine),
2. ONCASPAR (pegaspargase),
3. NEULASTA (pegfilgrastim),
4. PEGASYS (peginterferon alfa-2a),
5. PEGINTRON (peginterferon alfa-2b),
6. MIRCERA (methoxy polyethyleneglycol-epoietin beta),
7. SOMAVERT (pegvisomart).
8. CIMZIA (certolizumab pegol ),
a PEGylated recombinant humanized anti-TNFα Fab’ fragment)
PEGYLATED PROTEINSPEGYLATED PROTEINS
ARE DRUGS IF THE INTENDED -USE IS TO TREAT CUREARE DRUGS IF THE INTENDED -USE IS TO TREAT CURE
MITIGATE AND DIAGNOSE DISEASE IN HUMAN BEINGS:MITIGATE AND DIAGNOSE DISEASE IN HUMAN BEINGS:
Biological ProductBiological Product
Biological products include a wide range of products such asBiological products include a wide range of products such as
vaccines, blood and blood components, allergenics, somatic cells,vaccines, blood and blood components, allergenics, somatic cells,
gene therapy, tissues, and recombinant therapeutic proteins.gene therapy, tissues, and recombinant therapeutic proteins.
Biologics can be composed of sugars, proteins, or nucleic acids orBiologics can be composed of sugars, proteins, or nucleic acids or
complex combinations of these substances, or may be livingcomplex combinations of these substances, or may be living
entities such as cells and tissues.entities such as cells and tissues.
Biologics are isolated from a variety of natural sources:Biologics are isolated from a variety of natural sources:
Human, Animal, or Microorganism and may be producedHuman, Animal, or Microorganism and may be produced
by biotechnology methods and other cutting-edgeby biotechnology methods and other cutting-edge
Gene-based and Cellular biologics:Gene-based and Cellular biologics:
Example - often are at the forefront of biomedical research, andExample - often are at the forefront of biomedical research, and
may be used to treat a variety of medical conditions for which nomay be used to treat a variety of medical conditions for which no
other treatments are available.other treatments are available.
GENESIS OF BIOLOGICSGENESIS OF BIOLOGICS
THERAPEUTIC BIOLOGICAL PRODUCT
A therapeutic biological product is a protein derived from livingA therapeutic biological product is a protein derived from living
material (such as cells or tissues) used to treat or cure disease.material (such as cells or tissues) used to treat or cure disease.
A biologic is a medicinal product such as a vaccine, blood, or
blood component, allergenic, somatic cell, gene therapy, tissue,
recombinant therapeutic or living cells that are used
as therapeutics to treat diseases.
Biologics are created by biological processes, rather than
being chemically synthesized.
THERAPEUTIC EQUIVALENCE – US FDA
Therapeutic Equivalence (TE) :
Drugs classified as therapeutically equivalent can be substituted with
the full expectation that the substituted product will produce the
same clinical effect and safety profile as the prescribed product.
Drug products are considered to be therapeutically equivalent only if
they meet these criteria:
Pharmaceutical equivalents containing the same active ingredients,
dosage, and route of administration, strength.
Assigns therapeutic equivalence codes based on data that a drug
sponsor submits in an ANDA to scientifically demonstrate that its
product is bioequivalent (i.e., performs in the same manner as the
Reference Listed Drug).
BIOSIMILARS ..… CONCEPT
Biosimilars are generic version of biopharmaceutical
medicines which try to mimic products which are derived
from recombinant technology.
These are near identical products which use a separate
process for its bio formulation and need to pass strict
mandates of regulatory bodies like US FDA and EMEA in
As these compounds need to the process of manufacture
requiring fermentation and not traditional reverse chemistry
it is difficult to mimic bio identical compounds.
BIOSIMILAR …… CONCEPT
For complex molecular drug an innovator puts a drug in
market after proper approval for regulatory authorities:
obviously it has a brand name it is protected under patent
rights its structure may be correctly known or not known
Another manufacturer may discover complex molecule
using different source of cloning or process with structure
known or not known.
If this complex molecule has similar action as that of 1st
innovator …. Its biosimilar
There are clear cut differences in the manufacture process
and protein folding of biosimilars.
BIOSIMILARS …… contd
Due to the sophisticated nature of these bio-molecules and
their 3-D structure its an new area of research for
pharmaceutical scientists and drug regulators.
Apart from Biogenerics, a host of molecules especially have
Biosimilar compounds in endocrinology namely insulin,
growth hormone, PTH like peptides in India.
These need evidence based validation if they have clinically
relevant effects or side effects.
BIOSIMILARS ….. contd
Approved biologic version of innovator biopharmaceutical
products made by a different sponsor following patent and
exclusivity expiry on the innovator product.
Ex. Etanercept (Pfizer)
Because biosimilars are vastly more complex, other
manufacturers cannot guarantee that their version is exactly
identical to the original manufacturer's version, although it is
similar to the original biologic.
The subsequent manufacturer may use a slightly different
manufacturing process, which can occasionally produce
significantly different effects.
BIOLOGICS vs BIOSIMILARSBIOLOGICS vs BIOSIMILARS
Proteins produced by living cells, including monoclonal
antibodies, soluble receptors, receptor antagonists, novel
molecules derived by genetic engineering and other types of
proteins that can be used to treat human diseases.
Biosimilars may represent a cost-saving alternative to
Currently FDA has not provided details of the kind of testing
required to demonstrate sufficient similarity in efficacy and
safety for approval.
A similar production process does not ensure that the
biosimilar is functionally equivalent to a reference biologic.
Extensive human testing will be required.
BIOLOGICS vs BIOSIMILARS
Even though the FDA has been establishing standards for
licensure to ensure the safety and effectiveness of biosimilars
and issued a guidance in February 2012 , the FDA has not
approved a biological product as biosimilar or
Several companies are developing biosimilars and will almost
certainly submit applications for licensure under the new law.
It is not yet known when the first biosimilar product will be
on the U.S. market.
BIOSIMILARS – GLOBAL TRACKING
Over 425 biosimilars and 350 biobetters in the development
pipeline, from preclinical through marketed, plus over 350
companies involved globally.
US and EU patent and market and data exclusivity expirations have
been calculated for over 100 currently-approved reference products.
India is one of the leading contributors in the world biosimilar market.
India has demonstrated the greatest acceptance of biosimilars, which is
reflected from over 50 biopharmaceutical brands getting marketing
Indian biotechnology industry was 2.0 billion USD in 2006, 70% of
which is biopharmaceuticals. These are projected to reach up to
US$ 580 million by 2012.
BIOSIMILAR & BIOBETTER
biosimilars = 427; biobetters = 367; ref. products = 117
pipeline products (biosimilars + biobetters) = 788
Note, this study covers protein products, now nearly all recombinant proteins. Vaccines,
blood-derived, cellular, cultured tissues and other types of biologics are not included
LAUNCH OF BIOSIMILARS & BIOBETTERSLAUNCH OF BIOSIMILARS & BIOBETTERS
Note, "2011" indicates marketable before or in 2011.
BIOSIMILARS IN THE LAUNCH PIPELINE
"N.A." columin on right refers to pipeline products for which the reference product cannot be
determined (e.g., which of several interferon alfa-2 reference products a biosimilar seeks to
BIOSIMILARS – TOP COMPANIES
Harvest Moon Pharmaceuticals
Novo Nordisk A/S 25
Novartis AG 25
Pfizer Inc. 20
BioXpress Therapeutics S.A. 18
Biogen Idec 18
Lilly, Eli & Co. 18
Merck KGaA 17
Merck & Co., Inc. 16
Biocon Ltd. 14
Inbiopro Solutions Pvt Ltd. 14
Green Cross Corp. 14
Bio Sidus S.A. 13
LG Life Sciences Ltd. 13
Bioton S.A. 13
Sanofi S.A. 12
Bayer AG 12
Dong-A Pharmaceutical 12
Bolder BioTechnology, Inc. 12
Amega Biotech 11
AXXO GmbH 11
Chemo Group (Grupo Insud ) 11
BIOSIMILARS - IMPLICATIONS
Products that have been shown to be similar to the reference
product in appropriate comparative, head to head quality,
non-clinical and clinical studies.
Biosimilars made by a different sponsor following patent and
exclusivity expiry on the innovator product.
The follow-on manufacturer does not have access to the
originator's molecular clone bank and original cell bank.
Finally, nearly undetectable differences in impurities and/or
breakdown products are known to have serious health
Having similar action in human beings as that of HUMAN GROWTH
A monoclonal antibody, works by binding to (TNF-α). TNF-α is a
chemical messenger (cytokine) and a key part of the autoimmune
Acts as an anti-inflammatory and used to treat ankylosing spondylitis,
Crohn’s disease, psoriatic arthritis & psoriasis, rheumatoid arthritis,
A biosimilar of Johnson & Johnson’s blockbuster Remicade, which had
sales of US$8 billion in 2010.
DANGER OF BIOSIMILARS
The two biosimilar products have different origin
The two biosimilars may have same therapeutic effect
They may have different side effect and toxicology
Hence Biosimilars require thorough testing
Similarity between a biosimilar and its reference biotherapeutic product
should be evaluated in all respects (quality, safety and efficacy).
Purported copies of biotherapeutic medicines that have not undergone
head-to-head comparisons with an appropriate reference product put
patient safety at risk and should not be licensed via biosimilar pathways.
BIOSIMILARS vs SIMPLE DRUGS
Chemical structures of simple
drugs are known and are same in
patent and generic as well.
Generic version and innovators
of simple drugs the have same
The side effects are also same for
both generic & innovators of
Follow up drugs are usually
• Chemical structure and
composition is most likely to
be different and unknown.
• Always under brand name but
have same therapeutic use.
• The side effects may be
different for originator &
• Follow up drugs are not
generic in nature.
BIOSIMILARS - FDA APPROACH
Legislation in the 21st century has attempted to address this
by recognizing an intermediate ground of testing.
This is more testing than for small-molecule drugs proven to
be identical to each other, but less testing than for completely
In the European Union a specially adapted approval
procedure has been authorized for certain protein drugs,
termed similar biological medicinal products.
BIOSIMILARS – FDA APPROACH
This procedure is based on a thorough demonstration of
"comparability" of the "similar" product to an existing
Within the U.S., the Patient protection and Affordable Care
Act of 2010 created an abbreviated approval pathway for
biological products shown to be biosimilar to, or
interchangeable with, an FDA licensed reference biological
The acceptance of biosimilars may reduce the profitability
of biologics and the cost to the patients and healthcare
Introduction of biosimilars also requires a specifically
designed phamacovigillance plan.
BIOSIMILARS - FDA CONCERN
Unlike the more common small molecule drugs, biologics
generally exhibit high molecular complexity, and may be
quite sensitive to manufacturing process changes.
The follow-on manufacturer does not have access to the
originator's molecular clone and original cell bank.
Neither to the exact fermentation and purification
processes,nor to the active drug substance.
They only have access to the commercialized innovator
BIOSIMILARS - FDA CONCERN
Differences in impurities and/or breakdown products can
have serious health implications.
This has created a concern that copies of biologics might
perform differently than the original branded version of the
Consequently only a few subsequent versions of biologics
have been authorized in the US through the simplified
procedures allowed for small molecule generics namely:
Menotropins (January 1997) and Enoxaparin (July 2010), and
a further eight biologics through the 505(b)(2) pathway
PROCEDURAL STATUS - FDA
Genotropin, originally approved as a biologic drug under the
FD&C Act but now considered as reference product.
FDA has previously approved biologic products using
comparability, for example, Omnitrope in May 2006, but this like
Enoxaparin was also to a reference product.
On March 17, 2009, the Pathway for Biosimilars Act was introduced
in the House.
FDA was given the authority to approve biosimilars, including
interchangeable that are substitutable with their reference product,
as part of the Patient Protection and Affordable Care Act on March
None have yet been approved under the above said Act.
BIOSIMILARS – PAN GLOBE
SPONSOR DT. OF
(Pfizer, New York)
Sandoz April 2006
( Merck )
Celtrion July 2011
( Rituximab )
( Roche /Biogen )
Dr.Reddys July 2007
Biocon Oct 2011
• 12 years market exclusivity
• No exclusivity for supplements, new indications, dosing schedules,
dosage forms, delivery systems/devices or strengths
• But, exclusivity for “modification to structure”that results in change in
safety, purity or potency
First Interchangeable Biosimilar Product
• Up to one year of being only interchangeable product
• Can be shortened if unable to launch
BIOSIMILARS – INDIAN PLAYERS
India is exposed to vast opportunities in biosimilars.
Competent houses are already making great headway.
Govt has to develop the pathways for safe arrival of biosimilars in indian
Pharmacovigellence is going to play very prominent role in the advent
Lot of cautions precautions and warnings will be encountered.
A responsible role is required to be played by all and every one .
every one has to rise above all motives to provide safe biosimilars.
INDIA - BIOSIMILARSINDIA - BIOSIMILARS
Need to study the issue in detail
Need to organize expert body to take up the task
Need to identify the super experts
Need to listen from the mouth of horses
Evaluate the size of activity
Identify the inputs in terms of infrastructure experts facilities
finance, legislation under drugs and cosmetics rules
Strengthening of pharmaco-vigillence with special design
CRESP – DR. REDDY’S BIOSIMILAR
Darbepoetin alfa is a 37 kDa glyco-protein which was developed to be a hyper-
glycosylated long lasting form of recombinant human erythropoietin (rHuEPO).
Increased glycosylation results in higher sialic acid content per molecule. This is
responsible for increased half-life of darbepoetin alfa when compared to
Like all biopharmaceuticals, darbepoetin
alfa is synthesized in living organisms by
modifying their DNA using recombinant
CRESP - DARBEPOETIN
Mechanism of Action: DARBEPOETIN ALFA
Stimulates erythropoiesis by binding to erythropoietin receptors (EPO-R) on
Binding to EPO-R results in activation of the JAK-STAT signal transduction
Activation of the signal transduction pathway results in survival,
differentiation, proliferation, and maturation of Red Blood Cells (RBCs).
Cresp is available in the
• Single-use vials:
25 μg/1 mL and 40 μg/1 mL
25μg/0.42mL & 40μg/0.4mL
REDITUX – DRL’s 1ST
Rituximab is a 144 kDa chimeric mouse/human monoclonal antibody
consisting of a glycosylated IgG1kappa immunoglobulin with murine
light- and heavy chain variable regions (Fab) and human kappa and
gamma-1 constant regions (Fc domain).
Produced by using recombinant DNA technology in
Chinese Hamster Ovary (CHO) cells.
Binds to CD20 antigen which is expressed on
B-lymphocytes in non-Hodgkin’s lymphoma patients.
The binding of rituximab with the CD20 antigen is the first step
in the elicitation of its biological function.
It induces cell death through antibody-dependent cellular cytotoxicity
(ADCC), complement-dependent cytotoxicity (CDC) or apoptosis
Targeted B cell therapy via an infusion of rituximab ectively depletes B
cells resulting in a reduction in inflammation.
Therefore, it is also used to treat patients suffering from rheumatoid
DR. REDDY’s BIOSIMILAR
BIOCON - BIOSIMILAR PRODUCTS
BIOCON IS THE 4TH LARGEST PRODUCER OF RECOMBINANT HUMAN
INSULIN USING PROPRIETARY TECHNOLOGY.
BIOSIMILARS PRODUCT DESCRIPTION
ERIPRO Recombinant human erythropoietin
BIOMAB Bioximilar nimotuzumab (humanized mAb
targeting epidermal growth factor receptor)
NUFIL Filgrastim, recombinant G-CSF
MYOKINASE Recombinant streptokinase biosimilar
INSUGEN Recombinant human insulin
INTAS - BIOSIMILARS
BIOSIMILAR PRODUCT DESCRIPTION
NEUKINE Filgrastim ( recombinant G-CSF )
NEUPEG PEGylated G-CSF
INTALFA Recombinant human interferon alpha-2b
EPOFIT Recombinant erythropoietin
The only Indian Biotech facility that has been audited and approved for GMP by
the EMEA, MCC, South Africa and RCC DR of the Middle East countries for cGMP.
One of the Biosimilars developed has completed Phase 1 & 3 clinical trials in the EU.
RELIANCE LIFE SCIENCE - BIOSIMILARS
RLS was incorporated in 2001 and operates the country's largest
mammalian cell culture facility. Its UK subsidiary, Reliance Gene Medix
develops biosimilars for the European market.
70 % of the TOP line of the company is accounted for biosimilars.
BIOSIMILAR PRODUCT DESCRIPTION
RELIPOETIN Recombinant erythropoietin
RELIGRAST Recombinant G-CSF
RELIFERON Recombinant interferon alpha-2b
MIREL Recombinant reteplase
(tissue plasminogen activator)
INDIAN BIOSIMILAR MARKET
Indian biosimilar market in 2008 was estimated to be worth $200 million
& expected to reach $580 million by 2012.
More than 130 companies in the biopharmaceutical market in India.
Only 7-10 companies are involved in the manufacture of recombinant
products as of now.
• 48 drugs off patent within 10 yrs world wide ($ 73 billion)
Molecules in pipeline: Insulin, granulocyte colony-stimulating factor
(G-CSF), Interferons, monoclonal antibodies (MAbs).
mAb is the most demanding segment for many Indian players (mAbs
with a global revenues US$20 billion, the fastest-growing segment
within the pharmaceutical industry).
ARE BIOSIMILARS REALLY BIOSIMILARS
Terms ‘Biosimilars’, ‘Similar Biological Products’ & ‘Non-
Innovator Products’ etc often used interchangeably. Can
Non-Innovator Products or ‘Me-too’ products usually have
not been evaluated using comprehensive comparability
studies. They are not biosimilars.
This can be very important from the immunogenicity
EU DEFINITION OF BIOSIMILAR
According to the EU, a biosimilar product is a copy of an already
authorized biological medicinal product (The Reference Product ) with
demonstrated similarity in physiochemical characteristics, efficacy and
safety, based on a comprehensive comparability exercise.
Biological medicinal products are derived from living cells or organisms
and consist of relatively large & highly complex molecular entities that
are often difficult to fully characterize by currently available analytical
Because of the inherent variability of the biological system used as
manufacturing process, the resulting biological product will also display
a certain degree of variability (micro heterogenicity)
IMMUNOGENICITY OF IFN-β-1a PRODUCTS
All innovator products are immunogenic:
• Incidence of neutralizing antibodies (NAb):
Avonex 2-6% (13%); Rebif 12-28% (30 -39%); Blastoferon 8%;
loss of efficacy and treatment failure; abs are cross-reactive
• Removal of HSA from formulation of final product
NAb seroprevalence for Rebif New Formulation (no HSA) of 17.4%
compared to 27.3% for Rebif with HSA. Also fewer injection-site
• All non-innovator IFN-β-1a products contain HSA
and are likely to be immunogenic!
BIOSIMILAR REGULATORY SCENARIO - USA
BIOLOGICS PRICE COMPETITION & INNOVATION ACT”(BPCIA)
BPCIA provides a clear regulatory pathway for approval of “biosimilars”
Enacted on March 23, 2010, as a part of the Patient Protection and
Affordable Care Act
BPCIA establishes a biosimilar regulatory pathway under Section 351 of
the Public Health Service Act (PHSA), 42 U.S.C. §262
In very general terms, BPCIA authorizes FDA to approve
on similarity to an already-approved biologic (reference product
Reliance on the safety and efficacy findings of the reference product
(subject to data package protection, if applicable); and
reduced package of clinical and non-clinical safety and efficacy data for
BIOSIMILAR REGULATORY SCENARIO - EU
The Committee for Medicinal Products for Human Use (CHMP)
guidelines concerning Biosimilars:
• Concept of Biosimilar is applicable to any biological medicinal
product and more likely applied to highly purified products, which
can be thoroughly characterized
• Pharmacovigilance monitoring: the specific product given to the
patient should be clearly identified
• The active substance must be similar in molecular and biological
terms to the active substance of the reference medicinal product
Example: IFN alpha 2a is not similar to IFN alpha 2b.
• The same reference product throughout the comparability program
BIOSIMILAR REGULATORY SCENARIO - INDIA
Pre-Clinical studies are required
Phase I –II trials not required
Phase III –Non inferiority trial against innovator is required for the
Regulatory Process–Drug Controller General of India. –May involve
other regulatory bodies
Genetic Engineering Approval Council (GEAC)
Recombinant DNA Advisory Committee (RDAC),
Review Committee on Genetic Manipulation (RCGM),
Institutional Biosafety Committee (IBSC)
No separate approval process
No Exclusive Guidelines; applied on a Case-to-Case by Indian
Pharmacopoeia Commission (IPC) in collaboration with National
Institute of Biologicals (NIB)