This document discusses biosimilars and their manufacturing and regulation. It defines biosimilars as biological products that are similar but not identical to already approved biologics. Their manufacturing involves analyzing the reference product and replicating its structure through living cell cultures. Biosimilars undergo clinical trials to demonstrate similarity in safety and efficacy. Regulatory approval requires demonstrating comparability to the reference product. Issues include potential differences in efficacy and immunogenicity compared to the reference product.

1. BIOSIMILARS
DR. SARITA SHARMA
ASSOCIATE PROFESSOR
MMCP, MMDU

2. Biological products
 These are the medicines typically derived from living systems (protein or pieces of protein) and
produced using biotechnological tools
 Unlike other drugs biological drugs must be made in living systems like ; Yeast , Bacteria or animal cells
.
 Biologics include ; blood, vaccines ,blood components and recombinant therapeutic proteins .
 Biologics are very specific , highly effective medicines that improve health outcomes in many complex
conditions such as ; Crohns disease ,Ulcerative colitis , diabetes , rheumatoid arthritis , cancer, HIV,
osteoporosis, growth deficiencies and many .
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3. Biosimilars
 Biosimilars are the drugs or medicines that are similar ( close in structure and
function ) to biological drugs .
 Biosimilars are the drugs that are similar to innovator biologic , but not identical.
 Biosimilars are officially approved versions of original innovator product and can be
manufactured when the original products patent expires .
 They are similar in terms of quality , safety and efficacy to the already licensed , well
established reference medicinal product .
 Because of structural and manufacturing complexities, these biological products are
considered as similar but not generic equivalents of innovator biopharmaceutical
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4. Definition Of Biosimilars By Different
Authorities
1. As per EMA , A biosimilar medicine is a biological medicine that is similar to another
biological medicine that has been already authorized for use .
2. As per WHO , A biotherapeutic product which is similar in terms of quality , safety and
efficacy to an already licensed reference biotherapeutic product . They are termed as ‘
similar biologic products . (SBP)
3. As per US- FDA , A biopharmaceutical product highly similar to the reference product
without meaningful differences in safety , purity and potency . They are termed as Follow on
Biologics , (FOB)
4. As per HEALTH CANADA , Drugs that enters market subsequent to a version previously
authorized in Canada with demonstrated similarity to a reference biologic drugs . They are
termed as Subsequent Entry biologics . (SEB)
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5. History
 First approved in Europe by EMEA -2006 (Omnitrope = Genotropin)
 In US by FDA in 2015 – ZAXIRO( Filgrastim- For neutropenia)
 In India first biosimilar product was developed in 2000 .
Category Active substance Biosimilar Uses
Human growth
hormone
Somatotropin,
Genotropin
Omnitrope Growth deficiency
hormone
Recombinant product Epoetin Epoetin alfa HEXAL To treat anemia
Monoclonal antibody Infliximab Inflectra To treat chronic
inflammatory diseases
Hormones Insulin Glargine Abasaglar To treat hyperglycemia
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6. Biosimilar Vs Original Innovator Biologic
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 Biosimilars are not exact copies of originator biologic and neither these are expected to be the
exact replicas of innovator biologics as the manufacturing process through which the biologic is
made cannot be exactly duplicated by another manufacture .
 Biosimilars are similar to their innovator product but there being some minor differences in the
structure due to different manufacturing process involved, however these differences are not
clinically significant. Thus clinical outcomes of innovator biologics and biosimilars are identical.
 Though both innovator biologic and Biosimilars being protein in nature have immunogenic
potential, biosimilars tend to produce more adverse drug reactions than reference product.

7. Biosimilar Vs Original Innovator Biologic
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8. Difference Between Biosimilars And Generics
Biosimilars Generics
Produced by living cell cultures Produced by chemical synthesis
High molecular weight compounds Low molecular weight compounds
Complex dimensional structure Well defined structure
Unstable and sensitive to external conditions Stable
immunogenic Mostly non immunogenic
Clinically identical to their reference products but not
the same (active product likely to have variations)
Therapeutically equivalent with their reference
products (active product is always same)
Manufacturing is complex and variable Manufacturing is simple and consistent
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9. Difference Between Biosimilars And Generics
Biosimilars Generics
For approval regulators require clinical trials,
manufacturing and post-approval safety
monitoring programs similar to that of the original
innovator companies .
For approval regulators require bioavailability and
bioequivalence studies .
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10. Comparison Of Biologic Biosimilar And Generic
Process Biologic Biosimilar Generic
Manufacturing
 Produced by biological
process in host cells.
 Sensitive to production
changes-Expensive and
specialized production
facilities.
 Reproducibility difficult to
establish.
 Produced by biological
process in host cells.
 Sensitive to production
changes-Expensive and
specialized production
facilities.
 Reproducibility difficult
to establish.
 Produced by using
chemical synthesis.
 Less sensitive to
production changes.
 Reproducibility easy to
establish.
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11. Comparison Of Biologic Biosimilar And Generic
Process Biologic Biosimilar Generic
Clinical
development
 Extensive clinical studies ,
including phase I—III.
 Pharmacovigilance and
periodic safety updates
needed.
 Extensive clinical studies ,
including phase I—III
 Pharmacovigilance and
periodic safety updates
needed.
 Often only phase I studies.
 Short timeline for
approval.
Regulation
 Needs to demonstrate ,
comparability regulatory
pathway defined by
Europe (EMEA)
 Currently no automatic
substitution intended.
 Needs to demonstrate ,
similarity regulatory
pathway defined by Europe
(EMEA)
 Currently no automatic
substitution intended.
 Needs to show,
bioequivalence
abbreviated registration
procedures in Europe and
US
 Automatic substitution
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12. Manufacturing Of Biosimilars
 Once the patent for the original biologic expires ,It is legal for other manufacturers to create
a biosimilar.
 As the company of the original biologics is not obliged to share its manufacturing process , the
biosimilar manufacturers need to start from scratch .
 The different steps involved in manufacture of biosimilars are :
STEP 1:-
 First biosimilar manufacturers need to analyze the original biologic band go through published
data in order to reproduce the basic structure of the biologic.
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13. Manufacturing Of Biosimilars
STEP 2 :-
 Next they need to replicate the three dimensional
drug with the functional or what we called as the
clinically active parts . This is very complicated
process . Scientists need to depend on cultures of
living cells to assemble the drugs .
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14. Manufacturing Of Biosimilars
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15. Manufacturing Of Biosimilars
STEP 3 :-
 Once it has been made the new drug (biosimilar)needs to undergo rigorous evaluations to make sure that
its chemistry and function are similar to the original biologics .
 The new drug (biosimilar) also need to undergo functional test to make sure that it can bind to its target,
just as its original biologics.
STEP 4 :-
 The new drug needs to be compared to the original biologics in clinical trials to make sure it works just
as well as the original biologic and does not set off any unexpected effects in the body .
 Biosimilar manufacturers need to meet rigorous standards in terms of safety , purity and potency .
This whole process can take more than 10 years.
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16. Regulatory Guidelines For Approval Of Biosimilars
 In India regulatory requirements for marketing authorization of biosimilars were released in 2012.
 The data requirement includes :-
Analytical and Quality characterization Data :
 Comparability according to critical attributes of product including physicochemical properties , biological
activity, immunological properties , functional assays , purity etc.
Non clinical studies :
a. In vitro studies . E.g, cell based bioassay (cell proliferation assays or receptor binding assays).
b. In vivo studies : PD activity , immunogenicity, toxicity study , safety, mutagenicity, reproductive toxicity
and carcinogenicity studies.
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17. Regulatory Guidelines For Approval Of Biosimilars
Clinical studies :
i. Phase I : comparative PK and PD studies, PKPD relationship may be evaluated. PD evaluation can also be
done as part of phase III study .
ii. Phase II: dose ranging studies .
iii. Phase III : comparative efficacy and safetyimmunogenicity study. Equivalence design ,study is preferred.
iv. Phase IV : Post marketing , safety and immunogenicity data must be submitted.
Comparative clinical studies :
 Mechanism of action . Route of administration (dosage form and strength in comparison to licensed reference
product
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18. Regulatory Guidelines For Approval Of Biosimilars
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19. Issues Related To Biosimilars
 Efficacy issues :
 issue arising from difference between the bioactivity of biosimilar and their innovator
product.
 E.g ; Epoetin alpha products.
 11 Epoetin from 4 different countries ( Korea , Argentina , China , India ) were analyzed and
significant diversions from specifications for in vitro activity were observed.
 Deviations varied in range from 71 to 226%.
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20. Issues Related To Biosimilars
 Safety issues :
 These are the concerns regarding immunogenicity .
 The immune response , also called as immunogenicity .
 Since biologics are proteins, the body can develop antibodies to them over time , which might effect
their activity .
 E.g , Eprex .
 Eprex is a biosimilar of Epoetin alpha produced outside the US.
 Change in the manufacturing process by replacing Human albumin stabilizer by polysorbate 80
resulted in increased immunogenicity.
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21. Issues Related To Biosimilars
 Substitution :
 Prescribed chemical entity can be substituted by Generic chemical.
 Same rule of substitution cannot be applied in case of biosimilars due to the issues related to
safety and efficacy.
 Uncontrolled substitution of biologics can lead to severe consequences.
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22. Benefits Of Biosimilars
 Effective targeted therapy is used earlier in the disease .
 More patients have access to treatment .
 Biosimilars free up budget to innovative medicines .(low costs)
 More treatment options .
 More competition in the health care market.
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23. Conclusion
 Biosimilars are not generic versions of originator biologics, but they are affordable
alternatives that work similarly .
 For patients who have not begun as original biologic biosimilars may be useful alternative
for physicians to prescribe .
 However, only qualified health care professionals should be allowed to switch a patient from
an innovator biologic to a biosimilar and only if its not best for patients health .
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