Introduction to biopharmaceuticals Biologics History

1. PHARMACEUTICAL
BIOTECHNOLOGY
Semester-VI
COVID-19 is highlighting the importance of the biotechnology
field. Today, leaders from across the globe are leaning on
biotechnology and pharmaceutical companies with hopes of
possible solutions for the COVID-19 pandemic that range from
diagnostic assays and therapeutics to prophylactic vaccines.
Indian Biotechnologists, researchers and manufacturers have
accepted this challenge and have already made vaccine against the
COVID-19 onslaught.

2. Unit 1
Pharmaceuticals, biologics & biopharmaceuticals
• Introduction to pharmaceutical products
• Biopharmaceuticals and pharmaceutical
biotechnology
• History of the pharmaceutical industry
• The age of biopharmaceuticals
• Biopharmaceuticals: Current status and future
prospects

3. • Biotechnology encompasses any techniques that use living
organisms in the production of products having beneficial
to human being
• Drug is “a chemical substance that interacts with a living
system and produces a biological response”
• Drug product: As defined by FDA “a finished dosage form
that contains the active ingredient generally but not
necessarily in association with inactive ingredients”
• Pharmaceutics: Branch of pharmacy which deals with
• Study
• Fabrication
• Systematic approach to get an effective and stable
formulation without disturbing its quality
• Deals with technology involved in large scale
manufacturing

4. • Drugs may be good or bad
• Morphine is a drug of abuse, but is clinically most
effective painkiller, if still dangerous
• Heroin was the “heroic” drug until the severe dependency
issues
• All drugs are toxins and have side effects and can be
subject to abuse
• The effectiveness is measured by its therapeutic index–the
balance of benefit against undesired effects
• Very effective drugs lose their appeal if they also kill the
patient

5. Classification of drug:
• Ethical drugs:
• Those associated with the regulated pharma industry
• Generally prescription medicines covered by patents
• Generic drugs:
• Those ethical medicines off patent(patent has expired)
• Generic medicines are those produced without a license from the
innovator company when the patent or market exclusivity rights on
the innovator product have expired
• They are the same as prescription medicine when it comes to
bioavailability, routes of administration, form and factor, and even
performance
• Ethical/Prescription Medicines, on the other hand, are medicines that
are only available on the prescription of a doctor
• The significant difference between the two is the price
• Generic medicines tend to be cheaper and are usually available at
high discounts from the manufacturer/brand
.

6. • Pharmaceutical biotechnology consist of the combination of
two branches which Are “PHARMACEUTICAL
SCIENCE” and “BIOTECHNOLOGY”
• Classic example of biotechnological drugs-proteins
obtained from recombinant DNA technology
• Biotechnology now encompasses the use of tissue culture,
living cells or cell enzymes to make a defined product
• Principles of biotechnology are applied to the development
of drugs
• A majority of therapeutic drugs in the current market are
bioformulations, such as antibodies, nucleic acid products
and vaccines
• Future of pharmaceuticals belongs to protein based
therapeutics

7. • Pharmaceutical: A compound manufactured for use as
a medicinal drug
• Biopharmaceutical/Biologics: A biological
macromolecule or cellular component, such as a blood
product, hormone used as a pharmaceutical
• Pharmaceutical drug product manufactured in,
extracted from, or semi-synthesized from biological
sources
• Composed of sugar, proteins, nucleic acids and
maybe of living entities as cells and tissues
Issue: Some of the aspects of a biologic may be
undefined due to its complexity

8. • A biopharmaceutical which consists of sugars, proteins,
nucleic acids, living cells, or tissues, is a medicinal
product manufactured in extracted or semi-synthesized
from biological sources like humans, animals, or
microorganisms
• Different from traditional drugs synthesized from
chemical processes, the majority of biopharmaceutical
products are derived from biological processes including
the extraction from living systems or the production by
recombinant DNA technologies
• Transgenic organisms, especially plants, animals, or
microorganisms are potentially used to produce
biopharmaceuticals

10. • First generation biopharmaceuticals are un-engineered
murine monoclonal antibodies
• Simple replacement proteins displaying an identical amino
acid sequence to a native human protein
• Modern biopharmaceuticals are engineered, second-
generation products
• Engineering can entail alteration of amino acid sequence,
glyco-component of a glycosylated protein, or the covalent
attachment of chemical moieties such as polyethylene
glycol
• Engineering has been applied in order to alter
immunological or pharmacokinetic profile of protein, or in
order to generate novel fusion products

12. Introduction to pharmaceutical products
• Pharmaceutical substances form the backbone of modern
medicinal therapy
• Most traditional pharmaceuticals are low molecular mass organic
chemicals
• Some (e.g. aspirin)-originally isolated from biological sources
• Most are now manufactured by direct chemical synthesis

13. Traditional pharmaceutical sector
Two types of manufacturing companies
• Chemical synthesis plants
• Biotechnology based units
• Produce drugs from biological sources
• Described as products of biotechnology
• Products of biotechnology or chemical synthesis becomes
somewhat artificial
• Certain semi-synthetic antibiotics are produced by chemical
modification of natural antibiotics produced by fermentation
technology

15. Biopharmaceuticals and pharmaceutical biotechnology
• ‘Biologic’- Pharmaceutical product produced by
biotechnological endeavor
• Generally refers to medicinal products derived from
blood, as well as vaccines, toxins and allergen products
• Some traditional biotechnology-derived pharmaceutical
products fall outside the strict definition
• e.g. hormones, antibiotics and plant metabolites
• The term ‘biopharmaceutical’ was first used in the
1980s

16. • To describe a class of therapeutic protein produced by
modern biotechnological techniques, specifically via
genetic engineering or by hybridoma technology
• ‘Therapeutic protein synthesized in engineered (non-
naturally occurring) biological systems’
• More recently-nucleic acids used for purposes of gene
therapy too are generally referred to as
‘biopharmaceuticals’.
The term ‘biopharmaceutical’ refers to protein or
nucleic acid based pharmaceutical substances used
for therapeutic or in vivo diagnostic purposes, which
are produced by means other than direct extraction
from natural (non-engineered) biological sources

17. Term ‘biotechnology medicine’ is defined here as ‘any
pharmaceutical product used for a therapeutic or in
vivo diagnostic purpose, which is produced in full or in
part by either traditional or modern biotechnological
means’.
• Antibiotics extracted from fungi
• Therapeutic proteins extracted from native source
material (e.g. insulin from pig pancreas)
• Products produced by genetic engineering (e.g.
recombinant insulin)

19. • Biosimilar medicine:
• A biosimilar medicine is a medicine which is similar to a
biological medicine that has already been authorized (the
‘biological reference medicine’)
• Active substance of a biosimilar medicine is similar to the
one of the biological reference medicine
• Term used for a biologic drug that is produced using a
different cell-line, or different process than the one that
originally produced
• Used in same dose to treat the same disease
• Similar but not identical
• Biosimilar are similar to the original biologic but not
generic
• Due to difference in initial raw material

21. A brief history of drug discovery
 Medications were based mainly on herbal products (3000
BC)
 400 BC
o Hippocrates introduced the concepts of medical
diagnosis, prognosis, and advanced medical ethics
 900-1000
o The Arabic scientist, Avicenna, recorded an
encyclopaedia of medical description and treatment
 1700s
o William Withering introduced digitalis, an extract from
the plant foxglove, for treatment of cardiac problems

22.  1768
o John Hunter noted that scurvy was caused by the lack of
vitamin C
o He prescribed the consumption of lemon juice to treat
scurvy
 1796
o British physician, Dr Edward Jenner, discovered
vaccination
o He successfully experimented with smallpox inoculations
o German pharmacist Friedrich Wilhelm Sertürner isolated
morphine from opium, and it became both the first pure
naturally derived medicine and the first to be
commercialised

23.  1864
o Louis Pasteur discovered that microorganisms cause
diseases
o Devised vaccination against rabies
 1891
o Paul Ehrlich coined the term chemotherapy and
o Used synthetic chemicals to try and cure disease
 1899
o Aspirin was created and used for the treatment of fever

24.  1928
o Alexander Fleming discovered that Penicillium
mould was active against Staphylococcus bacteria
 1955-1960
o First effective polio vaccines developed by Jonas
Salk and Albert Sabin
 1961
o Ibuprofen was first synthesised
 1970
• Vaccines against rubella, chicken pox, pneumonia
and meningitis were developed

25.  1986
o Hepatitis B vaccine was the first vaccine to be
routinely produced by recombinant DNA technology
 2006
o HPV (Human papillomavirus )vaccine was developed

26. Origin
•The origin of the Pharmaceutical industry can be traced back
to the chemical industries (of the late nineteenth century) in
the upper RhineValley of Switzerland
•These industries were producing dyestuffs.
•When dyestuffs were found to have antiseptic properties, a
number of the industries turned into Pharmaceutical
industries
e.g. Hoffman-LaRoche, Sandoz, Ciba-Geigy etc.
The first known drug store was opened by Arabian
pharmacists in Baghdad in754

27. History of the pharmaceutical industry
• Barely 60 years old
• From very modest beginnings it has grown rapidly-100
million dollar-7,00,00,00,000 rupees in mid of 80s
• Current value is likely double
• There are well in excess of 10,000 pharmaceutical
companies in existence
• Although only about 100 of these can claim to be of
true international significance
• Manufacturing in excess of 5000 individual
pharmaceutical substances used routinely in medicine
• The first stages of development of the modern
pharmaceutical industry can be traced back to the turn
of the twentieth century

28. • At that time (apart from folk cures), the medical
community had only four drugs that were effective in
treating specific diseases:
• Digitalis-from foxglove-to stimulate heart muscle
• Quinine-from the barks/roots of a plant (Cinchona sp.)-to
treat malaria
• Pecacuanha (active ingredient is a mixture of alkaloids),
used for treating dysentery-obtained from the bark/roots
of the plant species Cephaelis
• Mercury, for the treatment of syphilis

29. • Lack of appropriate safe and effective medicines
• Low life expectancy in those times
• Developments in biology
• Realization of the microbiological basis of many
diseases
• Development in the principles of organic chemistry
• Future innovation in the pharmaceutical industry
• The successful synthesis of various artificial dyes, which
proved to be therapeutically useful, led to the formation
of pharmaceutical/chemical companies such as Bayer
and Hoechst in the late 1800s
• Bayer-aspirin in 1895

30. • Despite these early advances, it was not developed until
1930s
• The initial landmark discovery of this era -the discovery
and chemical synthesis of the sulpha drugs
• These are a group of related molecules derived from the
red dye, Prontosil rubrum
These drugs proved effective in the treatment of a wide
variety of bacterial infections
• Large-scale industrial production of insulin also
commenced in the 1930s
• Industrial-scale penicillin manufacture in the early 1940

32. • Ciba Geigy, Eli Lilly, Wellcome, Glaxo and Roche
developed in this time
• Over the next two to three decades-development of drugs
such as tetracyclines, corticosteroids, oral contraceptives,
antidepressants etc.
• Most of these pharmaceutical substances are
manufactured by direct chemical synthesis

33. The Sulfanilamide Disaster:
• In1937,S.E.Massengil Company created an elixir (liquid
form) of the antibiotic sulphanilamide using diethylene
glycol as solvent
• Diethylene glycol is a great solvent, but extremely toxic
• Unfortunately, at the time, there were no legal
requirement to test the toxicity of the formulation
• Resulted in the deaths of more than 100 people in the
U.S.

34. • Story of Taxol:
1955 :
• Plant screening project to discover new anticancer agents
• Screening of 35,000 plants
1967:
• Identification of cytotoxic ingredient from the bark of Pacific
yew tree-Taxol (Generic name)
1969 :
• 10 g of pure compound from 1,200 kg of bark
1988:
• A remarkable response rate of 30% in patients with
• Effective for cancers like ovarian, breast, and lung
• Ecological concerns a bout the impact on yew populations
• Currently produced by plant cell culture technology developed
by Phyton Biotech.
• The use of Taxus cell-line in a large fermentation tank

35. Indian pharmaceutical industry
• Indian pharmaceutical industry is the world's second-
largest by volume
• Lead the manufacturing sector of India
• First pharmaceutical company are Bengal Chemicals and
Pharmaceutical Works
• Still exists today as one of 5 government-owned drug
manufacturers
• Started in Calcutta in 1930
• The government started to encourage the growth of drug
manufacturing by Indian companies in the early 1960s.
and with the Patents Act in 1970

36. Present Indian Market Size- Rs. 400 Billion

37. Top ten pharmaceutical organizations in India
• Sun Pharma Industries-Vadodara
• Lupin Labs-Ankleshwar and Mumbai
• Dr. Reddy's Laboratories-Hyderabad
• CIPLA-Mumbai
• Aurobindo Pharma-Pondicherry
• Cadila Healthcare-Ahmedabad
• GlaxoSmithKline Pharma-Mumbai
• Torrent Pharma-Ahmedabad
• Wockhardt - Mumbai
• Ipca Laboratories-Mumbai

38. Milestones in pharmaceutical industry
• 1895: Aspirin (Bayer)
• 1922 Discovery of Insulin
• 1930: Sulphanilamide (Sulpha drugs)
• 1930: Large scale production of insulin
• 1940: Penicillin Production

39. Age of biopharmaceuticals
1953: Structure of DNA
1973: Genetic Engineering
1975: Monoclonal Antibodies
1980: Recombinant Insulin
>10.000 companies
100 international players
5000 pharmaceutical products
Top 5 drugs are bio-pharmaceuticals
50% of top 100 are bio-pharmaceuticals
>10.000 companies
100 international players
5000 pharmaceutical products
Top 5 drugs are bio-pharmaceuticals
50% of top 100 are bio-pharmaceuticals
• HUMULIN: Human insulin rDNA origin]
• Human insulin is produced by recombinant
DNA technology utilizing a non-
pathogenic laboratory strain of Escherichia
coli
• HUMULIN is a suspension of crystals
produced from combining human insulin and
protamine sulfate under appropriate
conditions for crystal formation
• The amino acid sequence of HUMULIN N is
identical to human insulin

40. • Biomedical research-broaden our understanding of the molecular
mechanisms underlining both health and disease
• Research undertaken since the 1950s has pinpointed a host of
proteins produced naturally in the body which have obvious
therapeutic applications
e.g. interferons, interleukins, which regulate the immune response;
growth factors such as erythropoietin, which stimulates red blood
cell production; and neurotrophic factors, which regulate the
development and maintenance of neural tissue
• While the pharmaceutical potential of these regulatory molecules
was generally appreciated, their widespread medical application
was in most cases rendered impractical due to the tiny quantities
in which they were naturally produced

41. • Recombinant DNA technology and monoclonal antibody
technology overcame many such difficulties
• Marked the beginning of a new era of the pharmaceutical
sciences
• Recombinant DNA technology has had a four-fold
positive impact upon the production of pharmaceutically
important proteins
• Many proteins of therapeutic potential are produced
naturally in the body in minute quantities e.g.
Interferons, Interleukins and colony-stimulating
factors(CSFs)
• Recombinant production allows the manufacture of any
protein in whatever quantity it is required

42. • Overcomes the problem of source availability
• Recombinant production allows the manufacture of any
protein in whatever quantity
• Overcomes problems of product safety
• Direct extraction of product from some native biological
sources has, in the past, led to the unknowing
transmission of disease
• e.g. transmission of blood-borne pathogens such as
hepatitis B, C and HIV via infected blood products and
the transmission of Creutzfeldt–Jakob disease to persons
receiving human growth hormone preparations derived
from human pituitaries

43. • Provides an alternative to direct extraction from
inappropriate/dangerous source material
• A number of therapeutic proteins have traditionally
been extracted from human urine e.g. fertility hormone
FSH
• Urine is not considered a particularly desirable source
of pharmaceutical products
• While several products obtained from this source
remain on the market, recombinant forms have now
also been approved

44. • Other potential biopharmaceuticals are produced
naturally in total dangerous sources
• Ancrod, for example, is a protein displaying anti-
coagulant activity and, hence, is of potential clinical
use; however, it is produced naturally by the
Malaysian pit viper (current brand name: Viprinex)
• Recombinant production in less dangerous organisms,
such as Escherichia coli or Saccharomyces cerevisiae

45. • Site-directed mutagenesis facilitate the logical introduction of
pre-defined changes in a protein’s amino acid sequence
• Such changes can be minimal, such as the insertion, deletion or
alteration of a single amino acid residue, or can be more
substantial, e.g. the alteration or deletion of an entire domain, or
the generation of a novel hybrid protein
• Such changes can be made for a number of reasons and several
engineered products have now gained marketing approval
• Despite the undoubted advantages of recombinant production, it
remains the case that many protein-based products extracted
directly from native source material remain on the market
• These products have proved safe and effective

46. • In certain circumstances, direct extraction of native
source material can prove equally/more attractive
than recombinant production
• This may be for an economic reason, e.g. if the protein is
produced in very large quantities by the native source and
is easy to extract/purify, as is the case for human serum
albumin
• Some blood factor preparations purified from donor
blood actually contain several different blood factors and
hence can be used to treat several haemophilia patient
types
• Recombinant blood factor preparations, on the other
hand, contain a single blood factor and hence can be used
to treat only one haemophilia type

47. • Genetic engineering and monoclonal antibody technology
underpinned the establishment of literally hundreds of start-up
biopharmaceutical companies in the late 1970s and early 1980s
• Many of these fledgling companies were founded by
academics/technical experts to take commercial advantage of
developments in the biotechnological arena
• Most of these early companies displayed significant technical
expertise, but lacked experience in the practicalities of the drug
development process
• Most of the well-established large pharmaceutical companies, on
the other hand, were slow to invest heavily in biotech research
and development
• However, as the actual and potential therapeutic significance of
biopharmaceuticals became evident, many of these companies
did diversify into this area

48. • Most either purchased small established
biopharmaceutical concerns or formed strategic alliances
• An example was the long term alliance formed by
Genentech and the well-established pharmaceutical
company, Eli Lilly.
• Genentech developed recombinant human insulin, which
was then marketed by Eli Lilly under the trade name,
Humulin
• Some biopharmaceutical substances showed little efficacy
in treating their target condition, and/or exhibited
unacceptable side effects…….
• Mergers and acquisitions also led to the disappearance of
several biopharmaceutical concerns

49. Amgen, Biogen and Genentech…………….
• Three pioneering biopharmaceutical companies
• Founded in the 1980s as AMGen (Applied Molecular Genetics)
• Amgen now employs over 9000 people worldwide, making it one
of the largest dedicated biotechnology companies in existence
• Its headquarters are situated in Thousand Oaks, California
• Focus upon developing novel (mainly protein) therapeutics for
application in oncology, inflammation, bone disease, neurology,
metabolism and nephrology
• Six of its recombinant products had been approved for general
medical use
• Aranesp’ and ‘Epogen’
• ‘Neupogen’ and ‘Neulasta
• ‘Kineret’
• Anti-rheumatoid arthritis fusion protein, Enbrel

50. • Biogen was founded in Geneva, Switzerland in 1978 by a group of
leading molecular biologists
• Headquarters are located in Paris and it employs in excess of 2000
people worldwide
• Developed and directly markets the interferon-based product,
‘Avonex’
• A number of hepatitis B-based vaccines sold by SmithKline
Beecham (SKB) and Merck
• By 2001, worldwide sales of Biogen-discovered products had
reached US$ 3 billion
• Biogen reinvests ca. 33% of its revenues back into R&D and has
ongoing collaborations with several other pharmaceutical and
biotechnology companies

51. • Genentech was founded in 1976 by scientist Herbert
Boyer and the venture capitalist, Robert Swanson
• Headquartered in San Francisco, it employs almost 5000
staff worldwide
• Has 10 protein-based products on the market
• These include human growth hormones (‘Nutropin’)
• Antibody-based products ‘Herceptin’ and ‘Rituxan’
• Thrombolytic agents ‘Activase’ and ‘TNKase’
• Has 20 or so products in clinical trials
• In 2001, it generated some US$ 2.2 billion in revenues,
24% of which it reinvested in R&D

52. Biopharmaceuticals: Current status and future prospects
• Approximately one in every four new drugs now coming on the
market is a biopharmaceutical
• By mid 2006, some 160 biopharmaceutical products had gained
marketing approval
• Biopharmaceutical market size is $239.8 Billion in 2019,
growing at a CAGR of 13.28% during the forecast period 2020-
2025.
• e.g. Procrit (treatment of anaemia-US$ 4.0 billion)
• Intron A (treatment of leukaemia-US$ 0.3 billion),
• Humulin (treatment of diabetes-insulin-US$ 1.0 billion) etc.
• The market value is estimated to surpass US$50 billion by 2010
• Products include a range of hormones, blood factors and
thrombolytic agents, as well as vaccines and monoclonal
antibodies

53. The rapid pace of scientific advancements enables a greater
insight about diseases at the molecular level. As a result,
Biopharmaceutical companies execute basic research in
collaboration with researchers to seek powerful tools and
molecular medicines to better understand human diseases.
While the basic science offers a foundation of drug
developments, the biopharmaceutical industry is thus,
largely driven by an increasing number of chronic diseases,
growing geriatric population and rising awareness towards
targeted therapy. Furthermore, to effectively address
untreatable diseases, the demand for biopharmaceutical
medicines across the world accelerates Biopharmaceuticals
in the global market.

54. • Among them many are protein-based therapeutic agents
• Two nucleic-acid-based products: ‘Vitravene', an antisense
oligonucleotide, and `Macugen', an aptamer.
• Many additional nucleic-acid-based products for use in gene
therapy or antisense technology are in clinical trials
• Many of the initial biopharmaceuticals approved were simple
replacement proteins (e.g. blood factors and human insulin)
• Understanding of the relationship between protein structure
and function has facilitated the more recent introduction of
several engineered therapeutic proteins
• Majority of approved recombinant proteins have been
produced in the bacterium E. coli, the yeast S. cerevisiae or in
animal cell lines Chinese hamster ovary (CHO) cells or baby
hamster kidney (BHK) cells

55. • Most biopharmaceuticals approved to date are intended for human
use, a number of products destined for veterinary application also
• Example-recombinant bovine GH (Somatotrophin), was approved
in the USA in the early 1990s and used to increase milk yields
from dairy cattle
• At least 1000 potential biopharmaceuticals are currently being
evaluated in clinical trials
• Most protein-based products likely to gain marketing approval
over the next 2-3 years will he produced in engineered E. coil, S.
cerevisiae or animal cell lines
• Plant-based transgenic expression systems may potentially come
to the fore, particularly for the production of oral vaccines

56. • Technological developments in genomics, proteomics have impact
upon the early stages of drug development
• By linking changes in gene/protein expression to various disease
states, technologies will identify new drug targets for such diseases
• Many/most such targets will themselves be proteins, and drugs will
be designed / developed specifically to interact with
• They may be protein based or (more often) low molecular mass
ligands
• Future innovations have impact upon pharmaceutical
biotechnology include the development of alternative product
production systems, alternative methods of delivery and the
development of engineered cell-based therapies, particularly stem
cell therapy
• Protein-based biotechnology products produced to date are
produced in either microbial or in animal cell lines
• Work continues on the production of such products in transgenic
based production systems, specifically either transgenic plants or
animals

57. • Virtually all therapeutic proteins must enter the blood in
order to promote a therapeutic effect
• Such products must usually be administered parenterally
(administered by some means other than oral or rectal
intake, particularly intravenously or by injection)
• However, research continues on the development of non-
parenteral routes which may prove more convenient, less
costly and obtain on proved patient compliance.
• Alternative potential delivery routes include transdermal,
nasal, oral and buccal (relating to the mouth) approaches
• Most progress to date has been recorded with
pulmonary-based delivery systems
• An inhaled insulin product ('Exubera') was approved in
2006 for the treatment of type I and II diabetes
.

58. A small number of whole-cell-based therapeutic products
have also been approved to date. All contain mature, fully
differentiated cells extracted from a native biological source.
Improved techniques now allow the harvest of embryonic
and, indeed, adult stem cells, bringing the development of
stem cell-based drugs one step closer. However, the use of
stem cells to replace human cells or even entire
tissues/organs remains a long term goal. Overall, therefore,
products of pharmaceutical biotechnology play an important
role in the clinic and are likely to assume an even greater
relative importance in the future