2. HISTORY OF BIOTECHNOLOGY
• The term was coined in 1917 by Karl Ereky, a
Hungarian engineer & professor who described a
technology based on converting raw materials into a
more useful product.
• 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:
3. • “Any technological application that uses biological
systems, living organisms or derivatives thereof, to make
or modify products & processes for specific use.”
4. BIOPHARMACEUTICAL
• A drug created by means of biotechnology, especially
genetic engineering:
• Primarily rDNA protein & Monoclonal antibody
• Typically derived from living organisms
(animal cells, bacteria, viruses & yeast)
5. Include:
• Therapeutic proteins (cytokines, hormones & clotting
factors), Insulin, DNA vaccines, monoclonal antibodies
• New experimental modalities such as gene therapy, stem
cell therapy & RNA viruses
6.
7. 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.
8. DEFINITION OF BIOSIMILARS
• According to WHO - SBP (Similar Biologic Product)
A biotherapeutic product which is similar in terms of
quality, safety and efficacy to an already licensed
reference biotherapeutic product.
9. • According to US FDA - FOB (Follow-On Biologic)
• A biological product that is highly similar to a U.S.
licensed reference biological product with no clinically
meaningful differences in terms of the safety, purity and
potency .
10. BIOSIMILARS IN INDIA
• Dr. Reddy’s and Biocon both brought biosimilar
versions of Roche’s (Basel) Rituximab to market.
• Zenotech laboratories – developing atleast 6
biosimilar versions of mAbs.
• Wockhardt have launched their EPO & Insulin.
• Reliance life sciences has launches 3 biosimilars
Relipoeitin, Religrast & Reliferon in domestic market
in 2008.
11. GENERICS
• Chemically & therapeutically equivalent to the
branded, original, low molecular weight chemical
drugs whose patents have expired
• Identical to the original product
• Most countries already have well-established
scientific standards & legal mechanisms for
authorizing generics
12. DIFFERENCE BETWEEN CHEMICAL
GENERICS & BISIMILARS
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 of Aspirin is 180
Da whereas Interferon-β is 19,000 Da
13. 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.
14. 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
15. 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
16. • 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
17. CHALLENGES FOR BIOSIMILARS
• Biosimilar is “similar” and no “generic” to the first
biologics.
• Competition- same companies market the original
and second-generation products and there may not be
a marked difference in price.
• Higher cost of development.
18. • Biopharmaceuticals are less stable than chemical based
pharmaceuticals and thus require cold chain distribution
and have a shorter shelf life.
• Brand development and high promotional activities.
19. ISSUES OF CONCERN WITH USE OF
BIOSIMILARS
Efficacy issues
• Differences between the bioactivity of the biosimilars
& their innovator products
20. • Study compared quality parameters (purity, content &
efficacy) of several biosimilar brands taken from the
Indian market & with those of the innovator drug
products.
• Carried out on 16 commercial brands covering 3
different biopharmaceuticals: pegylated G-CSF, G-CSF
& erythropoietin.
• Marked lack of comparability between biosimilars &
innovator products.
21. Safety issues
• Concerns regarding immunogenicity
• ↑ 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.
22. Pharmacovigilance
• Due to limited clinical database at the time of approval→
Vigorous Pharmacovigilance required
• Immunogenicity is a unique safety issue
• Adverse drugs reactions monitoring data should be
exhaustive
• Type of adverse event & data about drug such as:
• Proprietary name, International nonproprietary name
(INN) & dosage
23. Substitution
• Allows dispensing of generic drugs in place of
prescribed IP.
• Rationale for generics→ Original drugs & their generics
are identical & have the same therapeutic effect.
• Produce cost savings
24. Same substitution rules should not be applied:
• Decrease the safety of therapy or cause therapeutic
failure.
• Uncontrolled substitution → confounds accurate
Pharmacovigilance.
• Adverse event emerges after switching from IP to its
biosimilar without documentation → event will not be
associated to a specific product or it will be ascribed to a
wrong product.
25. Naming and labeling
• Generic adaptation of chemical medicines is assigned the
same name→ identical copies of the reference products
• Biosimilars require unique INNs, as this would facilitate:
Prescribing & dispensing of biopharmaceuticals
Precise Pharmacovigilance
26. STATUS OF REGULATIONS FOR BIOSIMILARS
GLOBALLY
• Strong need for regulations governing biosimilars.
• Implementation of an abbreviated licensure pathway
for biological products presents challenges, given the
associated scientific & technical complexities.
• US & India have recently covered these under their
respective Acts by bringing in applicable guidelines
for their evaluation & overall regulation.
27. WHO Guidelines
• Scientific basis for the evaluation & regulation of
biosimilars was discussed & agreement for developing
WHO Guidelines was reached at the first ‘WHO informal
consultation on Regulatory evaluation of Therapeutic
Biological Medicinal Products’held in Geneva, 2007
• Published guidelines on Evaluation of Similar Biological
Products with detailed recommendations on clinical
development in October 2009
28. Regulatory framework in EU
• Guidelines on similar biological products containing
biotechnology-derived proteins as active substance were
adopted by European Medicines Agency (EMEA) in
June 2006.
• Issued product specific biosimilar guidelines.
• In European Union, the first patent on
biopharmaceuticals expired in 2001 & first biosimilar
medicine was approved by EMEA in 2006.
29. Regulatory framework in India
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.
30. • 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).
31. 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.
