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1. Pharmacology
M.Pharm Sem_1
Cellular & Molecular Pharmacology 104T
Prepared by : Pal Rohit
Roll no: 47
BIOSIMILARS
K.B Institute of Pharmaceutical Education & Research

2. TABLE
OF
CONTENTS
Introduction to Biologics
Introduction to Biosimilars
Definitions
Principles for development of Biosimilars
Difference from Generics
Production of Biopharmaceutical
Manufacturing issues with Biosimilar
Concerns with Biosimilars
Role of Pharmacovigilance
Benefits of Biosimilars

3. INTRODUCTION TO BIOLOGICS
• A biologic, also known as a biologic medical product, or biopharmaceutical, is any
pharmaceutical drug product manufactured in, extracted from, or semisynthesized from
biological sources and used in treatment or prevention of disease.
• Biologic medicines generally made by using biotechnological methods like Recombinant DNA
technology, PCR, gene delivery ,genome editing (CRISPR).
• Biologics compared to the synthetic chemical molecules are 100 to 1000 times larger in size,
having several hundred amino acid and biochemically joined together in a defined sequence by
peptide bonds to form a polypeptide. Thus, structurally, biologics are more complex than low
molecular weight drugs.
• Ultimately biologics are proteins and due to the bigger size and high molecular weight (average
molecular weight of 150 Dalton per amino acid) it cannot cross BBB and also cannot pass
through stomach wall so ,biopharmaceuticals can be only given through parenteral route.

4. EXAMPLES
• Vaccines
• Therapeutic proteins
• Insulin
• Monoclonal antibodies
• Erythropoietin
• Enzymes
• Human growth hormone

5. INTRODUCTION TO BIOSIMILAR
• Biosimilars are the subsequent version of biologic medical products where patent protection
and marketing exclusivity have expired where they are authorized on the basis of similarity in
terms of quality , non-clinical and clinical parameters between biosimilar and reference
biologics.
• Unlike generics where the active components are completely identical biosimilars are not likely
to be completely identical.
• Because of structural & manufacturing complexities these biological products are
considered as similar but not generics equivalent of innovator biopharmaceuticals.
• The quality , safety and efficacy of a biosimilar product must be approved by relevant regulatory
body before marketing. So the different regulatory bodies have different definition for
biosimilars.

6. DEFINITIONS
• WHO :- A biotherapeutic product which is similar in terms of quality, safety and efficacy
to an already licensed reference biotherapeutic product.
• US-FDA :-A biosimilar is a biological product that is highly similar to a US-licensed
reference biological product notwithstanding minor differences in clinically inactive
components, and for which there are no clinically meaningful differences between the
biological product and the reference product in terms of the safety, purity, and potency of
the product.
• EMEA :-A biosimilar is a biological medicine highly similar to another already approved
biological medicine (the 'reference medicine'). Biosimilars are approved according to the
same standards of pharmaceutical quality, safety and efficacy that apply to all biological
medicines

7. The similarities among these regulatory agencies’ definition of a biosimilar can be distilled into two
main themes:
1. Biosimilars are not generics and are copies of already approved products that have proven
to be similar to the original product (i.e., reference product)
2. Biosimilars must possess similarity in quality, safety and efficacy to an approved biologic
product.
• However, the process of introducing a biosimilar to an innovator product is far more complex than
the relatively straightforward process of introducing a generic equivalent to an innovator product
based on a new chemical entity.
• the active substance of a biopharmaceuticals is large complex protein structures not a
single molecular entity that’s why active component in two products are highly unlikely to
be identical therefor unlike generics biosimilars are only similar not identical.
• In this way, biosimilars are "similar but not the same" or in other words biosimilars are "the twin
but not the clone" to the original biologic innovator product.

8. PRINCIPLES FOR DEVELOPMENT OF
BIOSIMILARS
• Developed through sequential process.
• Extensive comparative studies between reference drug and drug under development.
• Extent of testing of biosimilar is less than that of reference product.
• Product should meet acceptable levels of safety ,efficacy and quality with the
reference drug.

9. DIFFERENCE FROM GENERICS

10. PRODUCTION OF BIOPHARMACEUTICAL

11. 1ST APPROVED BIOSIMILARS
• India :- Biovac™ (hepatitis B vaccine, Wockhardt) in year 2000.
Use as vaccine for hepatitis B.
• USA :- Zarxio® (filgrastim, Sandoz Inc.) in March 2015.
Use to increase the neutrophils count in treatment of cancer or HIV.
• EUROPE :- Omnitrope® (somatropin, Sandoz Inc.) in 2006.
Use as a substitute of human growth hormone .

12. ISSUES WITH MANUFACTURING BIOSIMILARS.
• Biosimilars are the large complex protein molecules so variability in or changes to any step
of the manufacturing process for a biologic or differences between the manufacturing
processes for an originator and biosimilar can substantially impact the physicochemical and
functional properties of a biologic product.
• Most biological substances are labile and sensitive to heat, oxidation, and sometimes light.
Subtle differences in their manufacturing process may affect their quality attributes with a
possible impact on the safety and efficacy prole of the medicinal product.
• Apparently biosimilars are a biologic product so no. Of starting and raw material
are biological origin so their manufacturing process is conducted under mild physiological
conditions of temperature, pH, ionic strength, and so on and that their chemical nature (i.e.,
proteins, glycoproteins, polysaccharides) may support microbial growth.

13. • biologics thus pose a higher risk of contamination by micro-organisms, viruses, and
nonconventional infectious agents as compared to chemical drugs.
• That kind risk cannot be mitigated by a terminal sterilization step, which is not applicable to
heat labile substances.
• most biological substances cannot be administered orally without being digested. As a
consequence, biological medicinal products are mainly parenteral forms. Parenterally
administered medicinal products need to be sterile and free of pyrogens.
• Another particular feature of biologics comes from their capacity to raise an immune
response. Setting aside vaccines, such a response is not desirable since it can elicit the
production of antibodies that may neutralize the biological active substance or can induce
severe side effects by neutralizing endogenous factors.

14. CONCERNS WITH BIOSIMILARS
Immunogenicity.
Efficacy issues.
Switching.
Interchangeability and substitution.
Naming and labelling.

15. IMMUNOGENICITY
• Immunogenicity is the ability of a foreign substance, such as an antigen, to provoke an
immune response in the body of a human or other animal.
• Like all biologics, biosimilars are structurally complex proteins that are typically
manufactured using genetically engineered animal, bacterial or plant cell culture systems.
• When administered to patients, all therapeutic proteins have the potential to induce an
unwanted immune response (i.e., to stimulate the formation of antidrug antibodies [ADAs])
• The impact of immune responses can range from no apparent effect to changes in
pharmacokinetics (PK), loss of effect and serious adverse events.
• The best ex for this is Pure red cell aplasia (PRCA) caused by biosimilar of Epoetin alfa.

16. EPOETIN ALFA
• The concern regarding immunogenicity is highlighted by the increase in number of cases of
pure red cell aplasia associated with a specific formulation of epoetin alfa.
• In this there was increase in the number of cases of pure red cell aplasia associated with a
specific formulation of epoetin alfa.
• Pure red cell aplasia : PRCA refers to a type of anaemia affecting the precursors to red
blood cells but not to white blood cells. In PRCA, the bone marrow ceases to
produce red blood cells.
• In most patients who were treated with EPREX biosimilar of Epoetin alfa there
were production of neutralizing antibodies against endogenous epoetin which supressed
the production of RBC in the bone marrow.

17. • Most of the cases were noted outside the U.S.
• The most likely cause was subtle changes in the manufacturing process. In the formulation
Eprex, the human albumin stabilizer was replaced by polysorbate 80 and glycine.
• Polysorbate 80 is supposed to have increased the immunogenicity of Eprex by eliciting the
formation of epoetin-containing micelles or by interacting with leachates released by the
uncoated rubber stoppers of prefilled syringes.

18. EFFICACY ISSUES
• Studies done in the past have demonstrated the differences between the bioactivity of the
biosimilars and their innovator products.
• In a study comparing 11 epoetin alfa products from four different countries (Korea,
Argentina, China, India), the isoform distribution among these products was variable and
there were significant diversions from specification for in vivo bioactivity.
• For example, in vivo bioactivity ranged from 71 to 226%, with 5 products failing to fulfill their
own specification.
• in case of monoclonal antibody therapy or treating a transplant rejection or a cancer patient,
such variability would not be acceptable.

19. SWITCHING
• In this context, the term ‘switching’ means that patients can be treated with the same type
of biopharmaceutical produced by different manufacturers during their treatment period.
• It is important to emphasise that it is not just a question of originator vs biosimilar switches,
but also switches between biosimilars.
• As these biologics and biosimilars are not identical, it is intensely discussed whether
these switches between biological products may increase the risk of immunogenic adverse
effects or loss of efficacy.

20. INTERCHANGEABILITY AND
SUBSTITUTION
• Interchangeability or substitution means dispensing of generic drugs in place of prescribed
innovator products.
• The rationale behind substitution of chemical drugs is that the original drugs and their
generics are identical and have the same therapeutic effect. For majority of chemical
generics, automatic substitution is appropriate and can produce cost savings.
• However, the same substitution rules should not be applied to biosimilars, as it may
decrease the safety of therapy or cause therapeutic failure.

21. NAMING AND LABELLING
• The international non-proprietary (INN) system of naming was established by the World
Health Organization in 1953 to promote “clear identification, safe prescription and
dispensing of medicines to patients, and for communication and exchange of information
among health professionals and scientists worldwide.”
• Non-proprietary name is given according to their API which is acceptable in case of
chemical medicine because generics are same copies of innovator but in case of
biosimilars it's not acceptable .
• biosimilars require unique INNs, as this would facilitate prescribing and dispensing of
biopharmaceuticals and also aid in precise pharmacovigilance.
• However biosimilars share non-proprietary names with the respective innovator products.

22. • For example, Remicade, which is the reference product for Inflectra as well as Remsima,
share the same international non-proprietary name infliximab.
• There should be comprehensive labelling of biosimilars including the deviations from
innovator product and unique safety and efficacy data, which would assist the physician
and pharmacist in making informed decisions.

23. ROLE OF PHARMACOVIGILANCE
• Pharmacovigilance (PV or PhV), is the pharmacological science relating to the collection,
detection, assessment, monitoring, and prevention of adverse effects with pharmaceutical
products.
• Post-authorization pharmacovigilance is considered essential to guarantee the product’s safety
and efficacy over time; as part of a comprehensive risk management program, this includes
regular testing for consistent manufacturing of the drug.
• Pharmacovigilance is important in the biosimilars market because of the limited ability to predict
clinical consequences of seemingly innocuous changes in the manufacturing process and the
scientific information gap.
• Immunogenicity is a unique safety issue with biosimilars. However, lack of validation and
standardization of methods for detection of immunogenicity further implies the necessity for
robust pharmacovigilance.

24. • The adverse drugs reactions monitoring data should be exhaustive, including the type of
adverse event and data about drug such as proprietary name, international non-proprietary
name (INN) and dosage given.
• Pharmacovigilance systems should differentiate between licensed reference product and
biosimilar products so that effects of biosimilars are not lost in the background of reports on
licensed reference products.
• One of the greatest concerns about biological drugs is the risks associated with these
products over time because of the structural changes in the molecule, as these are derived
from microorganism. It is highly possible that the risk–benefit profile established at the time
of approval will change over time through expanded use, patient characteristics, and
patient exposure.
• Therefore, pharmacovigilance should be continued for biosimilars as long as the product is
in the market.

25. BENEFITS OF BIOSIMILARS
• biosimilars can be used in a large variety of diseases, such as cancer, cardiovascular
illnesses, haemophilia, autoimmune diseases such as multiple sclerosis
and rheumatoid arthritis, and rare genetic conditions such as Gaucher’s disease and Fabry
disease .
• Biosimilars are less costly than originator biologic agents primarily because biosimilars do
not have to undergo the intensive clinical development process associated with approval of
an originator.

26. • Due to its cost being lower than the original biological, biosimilars are more accessible to a
wider group of people and countries.
• It can allow high-quality health care to extend to developing countries and sensitive
populations.
• Approval of biosimilars create additional treatment options for often expensive brand-
name products. These options are good for patients, as there may be manufacturing
problems with a given biologic, in which case, having an approved biosimilar option can
help patients continue treatment.

27. REFERENCES
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