Biosimilars are biologic medicines that are similar to already approved biologic reference products, though due to structural complexities they are not generic equivalents. They must demonstrate similarity in terms of safety, purity and potency through comprehensive comparability studies. Biologics are large, complex molecules produced through biotechnology in living cells, whereas generics are identical small molecule chemicals. Due to minor manufacturing differences, biosimilars can have efficacy or immunogenicity issues not seen with generics. India regulates biosimilars through various agencies including the Central Drugs Standard Control Organization.

3. penicillin

4. • A standard definition of biotechnology was not reached
until the United Nations &World Health Organization
accepted the “1992 Convention on Biological Diversity” &
defined biotechnology as:
• “Any technological application that uses biological
systems, living organisms or derivatives thereof, to make
or modify products & processes for specific use”

7. What are biosimilars?
•Legally approved subsequent versions of innovator
biopharmaceutical products made by a different
sponsor following patent & exclusivity expiry of the
innovator product.
• Because of structural & manufacturing complexities,
• these biological products are considered as similar,
• but not generic equivalents of innovator
biopharmaceuticals.

9. Term By Definition
SBP (Similar
Biologic
Product)
WHO Similar to an already licensed reference
biotherapeutic product in terms of
quality, safety & efficacy
FOB
(Follow-On
Biologic)
US-FDA Highly similar to the reference product
without clinically meaningful differences
in safety, purity and potency
SEB
(Subsequent
Entry Biologic)
Canada Drug that enters the market subsequent
to a version previously authorized in
Canada with demonstrated similarity to a
reference biologic drug

10. Based on these different definitions, there are three
determinants in the definition of the biosimilar product:
1. It should be a biologic product.
2. The reference product should be an already licensed
biologic product.
3. The demonstration of high similarity in safety, quality &
efficacy is necessary.
Similarity should be demonstrated using a set of
comprehensive comparability exercises at the quality, non-
clinical & clinical level.

13. Biologic medicines are currently prescribed to treat a wide
variety of conditions, including:
1. Blood conditions: leuko/neutro/pancytopenias
2. Cancers: colon & breast ca or NHL
3. Immune system disorders: rheumatoid arthritis,
4. Psoriasis & crohn’s disease
5. Neurological disorders: multiple sclerosis
6. More than 400 biologics are in clinical trials
7. These include therapies for cancers, alzheimer’s
8. Disease, heart disease, diabetes, HIV/AIDS &
9. Autoimmune disorders.

14. Manufacturing of
Biopharmaceuticals
• Recombinant Protein formation
• CellTherapies
• ViralVaccines

17. Production of carrier
system
Inoculation with virus
Elimination of
reproducibility and
infectivity
Purification
Virus fragment

18. Heavier
• Unlike structurally well-defined, low molecular weight
chemical drugs, biopharmaceuticals are:
• High molecular weight compounds with complex three
dimensional structure
• For example, the molecular weight ofAspirin is 180 Da
whereas Interferon-β is 19,000 Da.

19. Larger
• Typical biologic drug is 100 to 1000 times larger than small
molecule chemical drugs.
• Possesses fragile three-dimensional structure as
compared to well-characterized one-dimensional
structure of chemical drug.

20. Difficult to define structure
• Small Molecule drugs → easy to reproduce & specify
by mass spectroscopy & other techniques.
• Lack of appropriate investigative tools to define
composite structure of large proteins.

21. Complex manufacturing processes
• Manufacturers of biosimilar products will not have access
to manufacturing process of innovator
products→Proprietary knowledge.
• Impossible to accurately duplicate any protein product.
• Different manufacturing processes use different cell lines,
protein sources & extraction & purification techniques →
heterogeneity of biopharmaceuticals

22. • Versatile cell lines used to produce the proteins have an
impact on the gross structure of the protein
• Such alterations may significantly impact:
• Receptor binding, Stability, Pharmacokinetics & Safety
• Immunogenic potential of therapeutic proteins→ Unique
safety issue→ Not observed with chemical generics

23. Chemical Biological
Produced by chemical
Synthesis
Produced by living cell cultures
Low molecular weight High molecular weight
Well-defined structure Complex, heterogeneous
structure
Mostly process-independent Strongly process-dependent
Completely characterised Impossible to fully characterise
the molecular composition and
heterogeneity
Stable Unstable, sensitive to external
conditions
Mostly non-immunogenic Immunogenic

24. Impact Safety & Effectiveness of biologic
Quantity of Acid–base variants & Glycosylation
Alterations in the three-dimensional structure of the Protein
Significant changes in
behaviour of the cells & changes in the protein
Even small changes in production
(Minor equipment/ Environmental variations)

25. • To assure high quality & consistency in final product,
production process requires a high level of monitoring &
testing throughout the process
• A biologic drug typically has around 250 in-process tests
during manufacturing, compared to around 50 tests for
small molecule drugs.

29. • Cytokines are hormone-like molecules that can control
reactions between cells.They activate cells of the immune
system such as lymphocytes and macrophages.
• Interferon is potent glycoprotein cytokine that acts against
viruses and uncontrolled cell proliferation.
• The FDA has approved a recombinant variant of IL-2,
aldesleukin (Proleukin), for treating renal cell carcinoma
• An IL-1 blocker, anakinra (Kineret), has been approved for
treatment of rheumatoid arthritis.
• Another, rilonacept (Arcalyst), has been approved

45. Erythropoietin:
• Erythropoietin is the hormone responsible for inducing
red blood cell production by the body’s bone marrow.
• Drugs such as epoietin alfa (Epogen, Procrit) and
darbepoetin alfa (Aranesp)
• increased the production of red blood cells.They are used
to treat
• anaemia associated with chronic kidney failure,
• cancer
• chemotherapy, and
• antiretroviral HIV therapy

49. Efficacy issues
• Differences between the bioactivity of the biosimilars &
their innovator products.
• Example
• 11 epoetin alfa products from 4 different countries (Korea,
Argentina, China, India) differ in efficacy due to difference
in the production process.

50. • Some studies compared quality parameters (purity,
content & efficacy) of several biosimilar brands taken
from the Indian market & with those of the innovator drug
products and showed -
• Marked lack of comparability between biosimilars &
innovator products
• Significant difference in the level of purity was observed
among various brands of biosimilars as per European &
Indian Pharmacopoeia standards

51. Safety issues
• Concerns regarding immunogenicity
• Example
• ↑ in no. of cases of Pure Red Cell Aplasia associated with
specific formulation of epoetin α
• Caused by the production of neutralizing antibodies
against endogenous epoetin.

52. • Most of the cases in patients treated with Eprex→
• Biosimilar of epoetin α
• Cause→ subtle changes in manufacturing process,
• ↑ immunogenicity and thus the adverse effects.

53. Pharmacovigilance
• Due to limited clinical database at the time of approval→
• Vigorous pharmacovigilance is required.
• Immunogenicity is a unique safety issue.
• Adverse drugs reactions monitoring data should be
exhaustive.

54. Similar biologics are regulated as per:
• The Drugs and Cosmetics Act, 1940
• The Drugs Cosmetics Rules, 1945
• Rules for the manufacture, use, import, export & storage
of hazardous microorganisms/genetically engineered
organisms or cells, 1989.
• Notified under the Environment Protection Act

55. • Apart from Central Drugs Standard Control Organization
(CDSCO), the office of Drug Controller General of India
(DCGI) two other competent authorities are involved in
the approval process
1. Review Committee on Genetic Manipulation(RCGM)
• Works under Department of Biotechnology (DBT)
• Regulates import, export, carrying out research,
preclinical permission, No objection certificate for clinical
trial (CT) .

56. 2. Genetic Engineering Approval Committee (GEAC)
• Functions under the Department of Environment (DoE)
• Statutory body for review & approval of activities
involving large scale use of genetically engineered
organisms & their products

58. Active
substance
Product name Launch
date in
India
Company
Epoetin alfa Epofit/Erykine Aug 2005 Intas
Biopharma-
ceuticals
Darbopoetin
alfa
Cresp Aug 2010 Dr Reddy’s
Laboratories
Insulin
glargine
Basalog 2009 Biocon
Reteplase Mirel 2009 Reliance Life
Scienes
Rituximab Reditux Apr 2007 Dr Reddy’s
Laboratories