This document discusses regulatory issues related to evaluating biotechnology-derived pharmaceuticals. It defines key terms like biopharmaceuticals, biosimilars, and biogenerics. The EU and US have different regulatory approaches and definitions. In India, products are currently referred to as biogenerics and regulated under Schedule Y, though new guidelines are being developed. The presentation outlines important considerations for preclinical safety testing of biologics, including relevant animal species selection, dose levels, routes of administration, and key study types needed like toxicity, immunogenicity, reproductive, and carcinogenicity assessments.

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Regulatory Issues for CROs
Evaluation of
Biotechnology-Derived
Pharmaceuticals
K.K. Tripathi, PhD
Adviser and Member Secretary, RCGM
Department of Biotechnology
Ministry of S&T, GOI
kkt@dbt.nic.in
The views expressed in this presentation are those of the author and they have nothing to do with the
regulatory authoriries in place and GOI

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Structure of the Presentation
Basics
• Defining Biotech Medicines, Biopharmaceuticals,
Biogenerics & Biosimilars !!!
• EU and USA scenario and perspectives
•Indian Viewpoint
Regulation
• EU and USA
• India

3. 3/27
What are Biopharmaceuticals? Compared to drug
•Biopharma industry-25 yrs old with >350 marketed
products.
•Term widely used but hardly defined by users
•Over 4 million entries on Google search
•Involves use of biotechnology and pharmaceutical
compared to drug
•Antsense oligos, RNAi, synthetic peptides and other
products mimic biopharma as well drug

4. 4/27
Worldwide off Patent Biotech Medicines often
referred as
Generic Biophamaceuticals, (USA)
Biogenerics, (USA)
Follow-on Biologics, (USA)
Biosimilars, (EU) (rDNA & hybridoma derived)
Off Patent Biologicals, (All)
and so on ,,,,,,,,,,,,,,,
Definition is Market and Commerce based

5. 5/27
Biotech medicines often
replace or supplement a
natural protein produced by
the body, satisfying medical
needs previously unmet by
chemical medicines
What Are Biotech Medicines?
•More than 325 million patients worldwide have been
helped by biotech medicines
•More than 50% of medicines in development are
biotech medicines

6. 6/27
EU View: Biosimilars are not generic pharmaceuticals
–Generics are clinically identical to their reference products
–Biosimilars can never be identical to their reference products
􀂃Due to the complexity & variability of a biological, the quality
profile is determined by the manufacturing process
–'the product is the process'
􀂃Differences in process are inevitable between different
manufacturers
–minor process differences can lead to marked differences in
clinical profile

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Biosimilars are similar, not identical, to original
biotech products
Biosimilars are similar……. ….Not Identical
Different cell lines
Different mfg process
Small differences in substrate and mfg process may affect
patient safety and clinical efficacy of the product

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Impact of small differences among biotech products
on efficacy and safety is unpredictable
Safety and efficacy can differ significantly with small
changes in –protein biophysical characteristics or –
formulation of the drug produc
Long term safety profile of biosimilars has yet to be
established
Prescribers and patients should be aware of this to
ensure appropriate introduction into clinical practice
Need to recognize safety and efficacy issue in both
approval process and introduction into clinical
practice of biosimilars

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INDIAN Scenario
 No Biosimilar, only Biogeneric as in USA
No Guidelines
 Schedule Y of Drugs and Cosmetics Act
 EMEA/ICH Guidelines
 More than 20 products approved so far
Guidelines to be put in place soon

10. 10/27
Biogeneric products approved so far in India
Sal No
1
2
3
4
5
6
7
8
9
10
11
12
Molecule
Human insulin
Erythropoietin
Hepatitis B vaccine
Human growth hormone
Interleukin 2
Interleukin 11
Granulocyte Colony
Stimulating Factor
Colony Stimulating Factor
Interferon2Alpha
Interferon 2Beta
Interferons Gamma
Streptokinase
Sal No
13
14
15
16
17
18
19
20
Molecule
Tissue Plasminogen
Activator
Blood factor VIII
Follicle stimulating
hormone
Teriparatide (Forteo)
Drerecogin (Xigris) alpha
Platelet Derived Growth
factor (PDGF)
Epidermal Growth factor
(EGF)
Eptacogalpha (r-F VIIa) r-
coagulation factor
Refer DBT Website: www.igmoris.nic.in

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The Primary Goals of Preclinical
Safety Evaluation are
• Identify an initial safe dose and subsequent
dose escalation schemes in humans
• Identify potential target organs for toxicity and
for reversibility
• Identify safety parameters for clinical
monitoring

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The Test Materials
Monoclonal antibodies, Cytokines, Growth factors,
Vaccines, Fusion proteins, Hormones, Chemically
synthesized peptides, Enzymes, Plasma derived
products, Receptors, Oligonucleotides, proteins
extracted from human tissue, biotransformed drugs
with small molecular weight as generic products of
Pharma, and Guess what more !!!!!!

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The Test Substances
•Investigational new drug or new entities
•Biologically similar to an already tested
and used drug or molecule as a biologic
• What to term it Biogeneric? Biosimilar?
Or !!!!!

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Comparability
 Evaluated on the basis of biochemical and
biological characterization (i.e., identity,
purity, stability, and potency).
 In some cases, additional studies may be
needed (i.e., pharmacokinetics, pharmaco-
dynamics and / or safety).

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Preclinical Safety Testing
Requirements
 Selection of the relevant animal
species;
 Age;
 Physiological state;
 Dose, route of administration, and
treatment regimen; and
 Stability of the test material under the
conditions of use.

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Approaches
 Conventional approaches to toxicity testing of
pharmaceuticals may not be appropriate due
to the unique and diverse structural and
biological properties.
 This includes species specificity,
immunogenicity, and unpredicted activities.
 Biological activity may be evaluated using in
vitro assays.

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Receptor / Epitope Distribution
 Knowledge of receptor/ epitope distribution can
provide greater understanding of potential in vivo
toxicity .
 Relevant animal species for testing of monoclonal
antibodies are those that express the desired epitope
and demonstrate a similar tissue cross-reactivity
profile as for human tissues.
 An animal species that does not express the desired
epitope may still be of some relevance for assessing
toxicity if comparable unintentional tissue cross
reactivity to humans is demonstrated.

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Species to be Studied
 Safety evaluation programs should normally include
two relevant species.
 one relevant species may suffice (e.g., when only
one relevant species can be identified or where the
biological activity of the biopharmaceutical is well
understood).
 In addition, even where two species may be
necessary to characterize toxicity in short term
studies, it may be possible to justify the use of only
one species for subsequent long-term toxicity
studies (e.g., if the toxicity profile in the two species
is comparable in the short term).

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When No Relevant
Species Exists
 The use of relevant transgenic animals expressing
the human receptor or the use of homologous
proteins should be considered.
 Pharmacological mechanism(s) may differ between
the homologous form and the product intended for
clinical use.
 Where it is not possible to use transgenic animal
models or homologous proteins evaluation in a
single species, e.g., a repeated dose toxicity study
of < 14 days duration that includes an evaluation of
important functional endpoints (e.g., cardiovascular
and respiratory).

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Administration / Dose Selection
 The route and frequency of administration as close as
possible to proposed clinical use.
 Pharmacokinetics and bioavailability of the product in the
species being used.
 Effects of volume, concentration, formulation, and site of
administration.
 The use of routes of administration other than those used
clinically may be acceptable if the route must be modified
due to limited bioavailability, limitations due to the route of
administration, or to size/physiology of the animal species.
 Two routes otherwise is not required.

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Dosage levels
 Dosage levels should be selected to provide
information on a dose-response relationship,
 Include a toxic dose and a no observed adverse
effect level (NOAEL).
 Products with little to no toxicity, it may not be
possible to define a specific maximum dose.
 In these cases, a scientific justification of the
rationale for the dose selection and projected
multiples of human exposure should be provided.
 Where a product has a lower affinity to or potency
in the cells of the selected species than in human
cells, testing of higher doses may be important.

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• Immunogenicity
• Antibody Formation In Humans
• Safety Pharmacology
• Pharmacokinetic studies
• Single Dose Toxicity Studies
• Repeated Dose Toxicity Studies
• Immunotoxicity Studies
• Reproductive Performance and Developmental
Toxicity Studies
• Genotoxicity Studies
• Carcinogenicity Studies

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Carcinogenicity Studies 2
 With some biopharmaceuticals, there is a
potential concern about accumulation of
spontaneously mutated cells (e.g., via
facilitating a selective advantage of
proliferation) leading to carcinogenicity.
 The standard battery of genotoxicity tests is not
designed to detect these conditions.
 Alternative in vitro or in vivo models to address
such concerns may have to be developed and
evaluated.

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