biologics development and regulatory authority involved in regulation of these products.

1. Drug development
and discovery in
biologics
ASHISH SHARMA
M.PHARM
CLINICAL Research

2. CONTENT
1.Introduction
2.Biologics & Biosimilars
3.Integrated discovery and development of antibodies
4.Market status of biologics
5.Overview of typical biologic manufacturing process
6.Therapeutic role
7.Biological target in therapy
8.Challenges
9.Regulation of biologics by CDSCO
10.Biologics vs small molecule
11.Conclusion
12.Reference

3. Biological or “Biologics” can be defined as product of which the
active Substance is produced by or extracted from a biological
source.
 Which Includes vaccines, blood, and blood components,
allergenic, somatic Cell, gene therapy, tissues, and recombinant
therapeutic proteins.
They are isolated from living sources- human, animal, plant,
fungal, Or microbial.
Biologics drugs are sometimes referred to as biologic response
Modifiers because they change the manner of operation of natural
Biologic intracellular and cellular action.

4. Biologics & Biosimilar!!
Biologics or biological products are medicines made
from living organisms through highly complex
manufacturing processes and must be handled and
administered under carefully monitored conditions.
A biosimilar is exactly what its name implies — it is a
biologic that is “similar” to another biologic medicine
(known as a reference product) which is already
licensed by the U.S. Food and Drug Administration
(FDA).

5. Biosimilars are highly similar to the reference
product in terms of safety, purity and potency,
but may have minor differences in clinically
inactive components. In approving biosimilars,
the FDA may require that manufacturers conduct
a clinical study (or studies) sufficient to establish
safety, purity or potency in one or more uses for
which the reference product is licensed and the
biosimilar seeks licensure.
Cont..

7. Integrated discovery and development of
antibodies
Target characterization &regent
generation
Critical reagent
generation
Assay development
Antibody generation
Hybridoma generation
Phase display
Screening for specific
attributes
bioassays

8. Cont….
Optimization of lead mAb
Antibody
engineering
Cell line
development &cell
banking
PK/PD
Pharmacology
Bioassay
Preclinical development
Process
development
Analytical
development
&qualification

9. Cont..
Preclinical development
Formulation
development
PK/PD
Pharmacology
Toxicology
Bioassay
Clinical manufacturing
Scale up & GMP
manufacturing
Toxicology
Bioassay

11. MARKET STATUS OF BIOLOGICS
 Study Period:2016-2024
 Base Year:2018
 Fastest Growing Market: Asia Pacific
 Largest Market: North America
The success of biologic drugs in the treatment of
major chronic diseases, notably cancer and
autoimmune diseases, has enabled big
pharmaceutical companies, like Eli Lilly and
Company, Bristol-Myers Squibb, Novartis,
AstraZeneca, and GlaxoSmithKline (GSK), to
invest in these products. In 2016, biologics
accounted for six of the top-eight drugs, in terms of
revenue.

12.  Humira (adalimumab), which was developed by
AbbVie for the treatment of rheumatoid arthritis,
psoriasis, Crohn’s, and other autoimmune diseases,
led to USD 16 billion in sales, as per the report, Top
15 Best-Selling Drugs of 2016.
Key Market Trends
 Vaccine Segment is Expected to Grow Fastest
during the Forecast Period
 The monoclonal antibodies segment held a
maximum share in 2018 due to higher usage of this
category of drugs in different therapeutic areas.
North America holds the Largest Market Share and
is Believed to Follow the Same Trend over the
Forecast Period
Cont…

13. Overview of typical biologics
manufacturing process

14. THEREPEUTIC ROLE
 Biologic drugs are used for treatment of
numerous diseases and conditions, and are
the most advanced therapies available. Some
biologic drugs are used for the treatment of
Crohn's disease, ulcerative colitis, rheumatoid
arthritis, and other autoimmune diseases.
Available biologics have
revolutionized cancer treatment, delayed or
reversed the course of immune related
conditions, changed the lives of people with
rare diseases, and have offered hope for many
patients who previously had no effective
treatment options for their condition.

15. Cont..
Disease in which
biologics are used:
Various cancers
Rheumatoid
arthritis(RA)
Ankylosing
spondylitis
Crohn's disease
Ulcerative colitis
Psoriasis

16. Age-related
macular
degeneration
Diabetic
retinopathy
Prevention
of pneumonia
AnemiaChronic migraine
Hepatitis B
Hemophilia
Cont..

17. Biological target in therapy
There are numerous biological target which are use in
treatment of various ailments:
Tumour necrosis factor α
TNFα is a pro‐inflammatory cytokine that has an important
role in inflammatory disease. Three biological anti‐TNFα
agents are approved for clinical use: two monoclonal
antibodies, infliximab and adalimumab, and the fusion
protein etanercept.

18. Adalimumab
Adalimumab (Humira) Recombinant human IgG1
monoclonal antibody
Rheumatoid arthritis In combination with
methotrexate for
(a) Treatment of moderate to severe active RA in
adults when the response to DMARDs including
methotrexate has been inadequate
(b) Treatment of severe, active and progressive RA in
adults not previously treated with methotrexate
Can be given as monotherapy in cases of
methotrexate intolerance or when continued
methotrexate is inappropriate.

19. CD2 on T lymphocytes
Alefacept
• Recombinant fusion protein of human
LFA‐3‐IgG1 Fc
US FDA approval for treatment of adults with
moderate to severe chronic plaque psoriasis who
are candidates for systemic therapy or
phototherapy

20. CD3 glycoprotein on T lymphocyte
Muromonab—CD3 (Orthoclone)
US FDA approval for the treatment of acute renal
allograft rejection, treatment of acute rejection after
heart or liver transplantation in patients resistant to
standard steroidal therapy
CD20
Rituximab (MabThera)
Treatment of patients with stage III–IV follicular
lymphoma who are chemo‐resistant or in their second
or subsequent relapse after chemotherapy
Treatment of previously untreated patients with stage
III–IV follicular lymphoma in combination with CVP
chemotherapy
Treatment of patients with CD20‐positive diffuse large
B‐cell NHL in combination with CHOP chemotherapy

21. CD11a
Efalizumab (Raptiva)
Treatment of adult patients with moderate to
severe chronic plaque psoriasis who have
failed to respond to, or who have a
contraindication to, or are intolerant of other
systemic therapies including ciclosporin,
methotrexate and PUVA
IgE
Omalizumab (Xolair)
Additional therapy to improve asthma control in
adult and adolescent patients with severe
persistent allergic asthma who have a positive
skin test

22. CHALLENGES
The discovery and development of biologics has
Numerous challenges some of which are below:
 Complex process: minor alteration at any of
the step in production cascade can lead to
drastic change in characteristic of end product.
 Safety implication: small difference in
production process can have major implication
on safety profile.
 Contamination: As biologics are from natural
origin so chances of contamination are high.
 Immunogenicity: biologics are specifically
prone to the induction of immunogenicity .

23.  Limited safety information: The predictability of
preclinical data to human is limited for biologics due to
species-specific action and immunogenic properties in
animal.
 Patient compliance: As majority of biologics are
administered by parental route so it is inconvenient in
long term therapy and affects compliance.
 Storage and shelf life: Most of biologics are
temperature and humidity sensitive ,susceptible to
microbial contamination products with short shelf-life.
 Adjuvant therapy: Monoclonal antibodies and immune
based therapies proves to be useful as adjuvant and
not mainline therapy.
 Aseptic environment: Most biologics manufacturing
requires elaborate biotechnological based technique
which requires aseptic environment.

24. REGULATION OF BIOLOGICS BY
CDSCO
 APPLICABLE GUIDELINES
1. RECOMBINANT DNA
SAFETY(GUIDELINES,1990)
2. CDSCO GUIDENCE FOR INDUSTRY,
2008
3. GUIDELINES AND HANDBOOKFOR
IBCS,2011
4. Generating preclinical and clinical data for
rDNA vaccines,dignostics and other
biological guidelines , 1999

25.  Types of Applications
Submission of various application forms to
regulatory agencies is as follows:
Stage Agency
involved
Application Approval
Manufacturing
license for test,
analysis and
examination
State FDA /
cdsco
Form 30 Form 29
Preclinical
studies
permission
RCGM Form C3 Form C6
Clinical trial Cdsco Form 44 Permission
letter

26. Stage Agency involved Application Approval
Manufacturing
and marketing
permission
Cdsco Form 44 Form 45/46
(finished product)
Manufacturing
license
State FDA/
CDSCO
Form 27D Form 28D
Registration and
import license
CDSCO Form 40/ Form 8 Form 21/ form 10
Cont..

27. RECENTLY APPROVED BIOLOGICS
Trade
name/proper
name
Indication for use Manufacturer Approval date
Alinity s HIV Ag/Ab
Combo assay
Human
Immunodeficiency
Virus Types 1 and 2
presence of anti-
HIV-1/HIV-2 and
HIV-1 p24 antigen.
The assay is also
intended for use in
testing serum and
plasma specimens
Abbott GMbH &
Co. KG
Abbott
Laboratories
07/23/2019
Alinity s Anti-HCV
assay
Hepatitis C-virus
Encoded Antigens
The Alinity s Anti-
HCV assay is a
chemiluminescent
micro particle
immunoassay
(CMIA) used for the
qualitative detection
of antibodies to
hepatitis C virus
(HCV) in human
serum and plasma
specimens.
Abbott GMbH &
Co. KG
Abbott
Laboratories
07/09/2019

28. Trade
name/proper
name
Indication for use manufacturer Date of
approval
DENGVAXIA
Dengue
Tetravalent
Vaccine, Live
Dengue Tetravalent Vaccine,
Live is indicated for the
prevention of dengue disease
caused by dengue virus .
Dengue Tetravalent Vaccine,
Live is approved for use in
individuals 9 to 16 years of
age.
Sanofi Pasteur
Inc.
05/01/2019
ESPEROCT
Antihemophili
c Factor
(Recombinan
t
For use in adults and children
with hemophilia A for: (1) on-
demand treatment and
control of bleeding episodes,
(2) perioperative
management of bleeding,
and (3) routine prophylaxis to
reduce the frequency of
bleeding episodes.
Novo Nordisk,
Inc.
02/19/2019

29. BIOLOGICS VS SMALL
MOLECULE
SMALL MOLECULE BIOLOGICS
General properties
Low molecular weights (0,1 - 1
kDa); usually chemically and
thermally stable, wide range of
polarity.
Very large molecular weights >1
kDa; generally polar, sensitive to
heat, easily degraded (with the
exception of some long-lived types
such as monoclonal antibodies)
Selectivity, safety
Rather promiscuous, usually bind
to various off-target sites,
rendering side-effects or toxicity.
Highly specific to the targets,
generally of lower toxicity
Business aspects
Low prices for SM drugs.
Typically, very high prices for
biologics treatments. This is
regarded as one of the reasons
biologics appear to be delivering
better overall economic returns,
compared to SMs.

30. Cont..

31. CONCLUSION
 Biologics and small molecule are
complementary to each other. They are
the two faces of the same coin and are
complementary to each other as they
are developed with the same objective
of ameliorating the disease .
 Based on validated target, suitable
approach either in the form of small
molecule or biologics, either singly or in
combination has to be pursued.

32. Reference
 https://cen.acs.org/articles/95/i33/Contract-
services-biologics-evolve.html
• Mordorintelligencecom. Mordorintelligence
com. [Online]. Available from:
https://mordorintelligence.com:81/industry-
reports/biologics-market
• https://www.ncbi.nlm.nih.gov/pmc/articles/P
MC1860592/
• https://www.biopharmatrend.com/post/67-
will-small-molecules-sustain-
pharmaceutical-race-with-biologics/

33. Johnston SL. Biologic therapies: what and when? [published correction
appears in J Clin Pathol. 2007 Mar;60(3):336]. J Clin Pathol. 2007;60(1):8–17.
doi:10.1136/jcp.2005.032300