Definition of biopharmaceuticals and biosimilars, Steps involved in manufacturing biopharmaceuticals, Points of differences between Biosimilars and Chemical Generics, Related issues with biosimilars

1. Abu Sufiyan Chhipa
M. Pharm
(Pharmacology) I sem.

2.  A biopharmaceutical is as drug created by means of
biotechnology, especially genetic engineering that
primarily involves rDNA or monoclonal antibody
techniques.
 These are typically derived from living organisms
(animal cells, bacteria, virus and yeast).
 Examples include: Therapeutic proteins (cytokines,
hormones, clotting factors), insulin, DNA vaccines etc.

3. Identify the human DNA sequence for the desired protein.
Isolate the DNA sequence
Selection of vector

4. Insert the gene into genome of host
Modification of cells (rDNA technology)
Separation, amplification and collection of
biopharmaceutical

6.  Biosimilars are legally approved subsequent versions of
innovator biopharmaceutical products made by a
different sponsor following patent and exclusivity expiry
of the innovator product.
 Because of structural and manufacturing complexities,
these biological products are considered as similar but
not generic equivalents of innovator
biopharmaceuticals.

7.  WHO: A biopharmaceutical product Similar to an already
licensed reference biotherapeutic product in terms of
quality, safety and efficacy. They are termed as “similar
biologic product (SBP).”
 US-FDA: A biopharmaceutical product highly similar to the
reference product without clinically meaningful differences
in safety, purity and potency. They are described as “Follow
on Biologic (FOB)”.
 CANADA: Drug that enters the market subsequent to a
version previously authorized in Canada with demonstrated
similarity to a reference biologic drug. They are termed as
“Subsequent entry biologic(SEB)”

8.  It should be a biologic product.
 Reference product should be an already licensed
biologic product.
 The biosimilar should demonstrate a high similarity of
safety, quality and efficacy to that of the reference
product.
 Similarity should be determined by comparing the
biosimilar product with the reference product based on
quality, non clinical and clinical studies.

9.  Generic drugs are chemically and therapeutically
equivalent to the branded, original, low molecular
weight chemical drugs whose patents have expired.
 In other words, their pharmacological effects are exactly
the same as those of their brand-name counterparts.

11.  Unlike structurally well defined, low molecular weight
chemical drugs, biopharmaceuticals are “High
molecular weight compounds with complex three
dimensional structure.”
Example:
Molecular weight of Aspirin (chemical generic) is 180Da
Molecular weight of interferon (biosimilar) is 19000Da

12.  A typical biologic drug is 100 to 1000 times larger than
small molecule chemical drugs.
 Biologics posses a complex three dimensional structure
whereas chemical generics have characterized one
dimensional structure.

13.  Due to the lack of knowledge of manufacturing process
of innovator drug (proprietary knowledge) to the
biosimilar manufacturers, it is impossible to accurately
duplicate a protein product.
 As different manufacturing processes are used, it leads
to heterogeneity of biopharmaceuticals.
 Such alterations significantly affect the
pharmacokinetics ,pharmacodynamics and safety of the
drug.
 Such unique safety issues are not observed with
generics.

14. BIOSIMILARS
 Produced by living cell
cultures.
 High molecular weight
compounds.
 Complex dimensional
structure.
 Unstable and sensitive to
external conditions.
 Immunogenic
GENERICS
 Produced by chemical
synthesis.
 Low molecular weight
compounds.
 Well defined structure.
 Stable
 Mostly non-immunogenic.

16.  Issues arising from differences between the bioactivity
of biosimilars and their innovator products.
Example: Epoetin alpha products
 11 epoetin from 4 different countries(Korea,Argentina,
China, India) were analysed and significant diversions
from specifications for in vivo activity were observed.
 Deviation varied in the range from 71 to 226%.

17.  These are concerns regarding immunogenicity.
Example : Eprex
 Eprex is a biosimilar of epoetin alpha produced outside
the US.
 Change in manufacturing process by replacing human
albumin stabilizer by polysorbate 80 resulted in
increased immunogenicity.
 Resulted in increased cases of pure red cell aplasia
caused by the production of neutralising antibodies
against epoetin.

18.  Prescribed chemical entity can be substituted by generic
chemical.
 Same rule of substitution cannot be applied in case of
biosimilar due to the issues related to safety and
efficacy.
 Uncontrolled substitution of biologics can lead to
severe consequences.

19.  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.

20.  Should be authorized using complete dossier.
 Rationale for the choice of reference biologic provided
by the manufacturer.
 The reference biologic selected should be used in all
comparative studies during the development of
biosimilar.
 Licensed in India and should be an innovator product.
 An existing similar biologic cannot be used as a
reference biologic.

22.  Molecular biology considerations:
These include details regarding host cell cultures,
vectors, gene sequences, promoters etc.
They also include post translational modifications:
Glycosylation, oxidation, deamidation, phosphorylation
etc.
 Manufacturing Procedure
 Product characterization:
Includes physicochemical properties, biological
activity, purity, contamination and strength.

23.  Conducted with the final formulation.
 Dosage form, strength and route of administration
should be same as that of RB.
 Prior to conduct of studies statutory approvals from
respective institutional biosafety committee (IBSC) &
institutional animal ethics committee (IAEC) should be
submitted.

24. 1. Pharmacodynamic studies
 In-vitro studies
Done by in vitro cell based bioassay (cell proliferation
assays and receptor binding assays).
 In vivo studies
Performed for more accurate results on laboratory
animals.

25. 2.Toxicological studies
 Repeat dose toxicity studies in relevant species is
required to be conducted.
 Other toxicological studies (mutagenicity,
carcinogenicity) are not generally required.
3. Immune responses in animals
 Test serum samples tested for reaction to host cell
proteins.
 Immune toxicity is evaluated in target tissues by
histopathology for the presence of immune complexes.