Strictly private and confidential
Golden Jubilee Celebrations of “Indian Drugs”
Mumbai
Saturday, 8 th March, 2014
1

Strictly private and confidential
• After independence, to manufacture any new drug was not possible because of prevailing system of product patents.
• The Indian consumer was denied the use of several life saving drugs which were launched internationally.
• Beecham introduced the semi-synthetic penicillin, Ampicillin in Europe in the early 60’s. They were unwilling to market this drug in India except on terms and conditions which were not acceptable to Indian government.
• Same was also the case with the Cardiac Drug, Propranolol, introduced by
ICI internationally in the mid 60s.
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Strictly private and confidential
Indian Industry fought to amend the 1911 Patent Act, resulting in the enactment of Indian Patent Act 1970, passed in September 1972.
“All product patents for Drugs and Agricultural chemicals were abolished and only process patents were allowed for a period of 7 years from the date of filling or 5 years from the date of acceptance, which ever is earlier”
It was a dawn of a golden age of the Indigenous Pharma Industry.
3

Strictly private and confidential
Original process of HOFFMAN-LA-ROCHE:
(USP. 3109843, dated 5-11-1963)
Cl
NH
2
1. BzCl
ZnCl
2
,

2.Hydrolysis
Cl
MeI
Base, Hydrolysis
Cl
( 40% )
Me
NH
O
NH
2
O PTS - Cl
Base
1. ClCH
2
COCl
2. Hexamine
Cl
Cl
H
N SO
2
O
Me
N
O
N
CH
3
NCL Process:
NO
2 PhCH
2
CN
NaOH
Cl
Me
NH
O
DIAZEPAM
Cl
Me
N
O
N
Cl
N
O
Me
2
SO
4
Fe,H
Cl
DIAZEPAM
Commercialized by Cipla in 1973
4

Avra
Strictly private and confidential
(Vinblastine and Vincristine)
N
OH
CH
3
H N
N
O
CH
3 O
O
CH
3
H
N
R
H
HO
O
VINBLASTINE: R=Me
CH
3
CH
3
O
O
CH
3
O
VINCRISTINE: R=CHO
5

(Anti Inflammatory, Anti Rheumatic)
BOOTS Process (GB 971 700:2.2.1961):
( A )
CH
3
COCl
AlCl
3
NH
2
OH 1/
2
H
2
SO
4
O
( B )
CH
3
N
OH
Cl CH
2
CO
2
Et
NaOEt,EtOH
Strictly private and confidential
H
3
C
O
O
OEt
1.NaOH
2. H
CH
3
CN
NaOH
Cheminor’s Approach:
( B )
O
CH
3
H
2
,Raney-Ni
( C )
CH
3
OH SOCl
2
NaCN
( D )
CH
3
Cl
CH
3
CHO
CH
3
CO
2
H
6

Strictly private and confidential
• Initiated in 1959; prevailing price $ 460/kg aimed to bring down to $ 350/kg
• Based on original Folkers Route; 12 steps synthesis carried out on Pilot Scale.
Completed in 1963 - Vitamine B6 price dropped to $ 80/kg in 1960.
• New Chemical Synthesis: (Kondratyers of USSR)
O
O
N
X O
X
O
CO
2
H
CO
2
H
HO N
Substituted Pyridines
Merck Process: NCL approach (1965 - 73)
H
2
N CH
3
CO
2
H
EtOH
HCl
H
2
N CH
3
CO
2
Et.HCl
H
2
N CHO
OHC
H
N CH
3
CO
2
Et
P
2 o
5
O
N
CH
OEt
3
O
O
1. 180 °C
2. HCl
H
3
C
HO
CH
2
OH
CH
2
OH
N .HCl
1960, Price $80/kg
1965, Price $55/kg
1970, Price $30/kg
Project failed - RM price was higher than the prevailing market price
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Strictly private and confidential
(Based on Roche approach)
CH
3
COCH
2
CO
2
Et
O
N
CH
3
CO
2
Et
NH
3
SO
2
Cl
2 CH
3
COCHClCO
O
N
CH
3
CO
2
NH
2
P
2
2
Et
O
5
H
2
N CHO
O
N
CN
CH
3
O
O
180 °C
O
O
HCl
HO
HO
H
3
C
H
3
C N
Technology was implemented by Lupin in 1985
N
CH
2
OH
CH
2
OH
.HCl
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Strictly private and confidential
HO
O
HN
O
O
N
N
3
AZT
AIDS (Acquired Immunodeficiency Syndrome), is caused by infection with Human Immunodeficiency Virus (HIV).
Twenty years ago, an AID Diagnosis was equivalent to a death sentence. The introduction of AZT, First AIDS drug in 1987 offered hope.
In 1985, Scientists at National Cancer Institute found that AZT, a molecule first synthesized in 1964 prevented HIV from multiplying in cultured human cells.
US FDA approved AZT for use against AIDS in early 1987 and
Burroughs Wellcome began marketing the drug under the trade name “RITROVIR”.
The initial cost of AZT (A years supply) costs ~10,000 USD per patient.
Most of the under developed countries con’t afford.
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Strictly private and confidential
Production of AZT
HO
O
HN
O
O
N
HO OH
1. PhOCO
2
2. NaHCO
3
Ph
3. DMF
HO
O
O
N
O
N
HO
Rama Rao's approach:
HO
O
HN
O
O
OH
N
1. PhOCO
2
2. NaHCO
3
Ph
3. DMF, 150 o
C
HO
O
OH
HO
N
O
O
N
Avra
1. Br
2
2. H
2
, Pd/C
HO
O
HN
O
O
N
HO
1. LiN
2. H
+
3
HO
O
HN
O
O
N
N
3
1. Ac
2
2. HBr
Beta-Thymidine
1. Raney Ni, H
2
2. NaOMe, MeOH
AZT
O, Py
AcO
O
HN
O
O
N
OAc
Br
J. C. S. Chem. Commun., 1994, 1255
US Patent No. 5596087 (Jan 1997)
10

Strictly private and confidential
• HIV virus has already affected over 45 million people world over in the last 2½ decades.
• It is estimated by the United Nations that 80 to 90 million
Africans alone will die of AIDs by 2025
• In India HIV infected population may be more than 25 million by 2020
• Cipla marketed AZT in India in 1995 at a price of 30 cents/tablet
11

• HIV was and is an Epidemic in South Africa. In 2001, the cost of Anti-Retroviral Drugs (ARVs) range between $ 12,000 to 15,000 USD per patient per year.
• In that year South Africa allowed generic production of ARVs for treating HIV patients, despite the fact they were covered by patents and 40 MNCs bought litigation against South
Africa for its act.
• At that time Cipla offered to make them available at $ 300 per patient per year (~ 1/40 th cost)
• After massive international protests in favour of public health rights, the Governments of several developed countries backed the South Africa and the case was dropped in April that year.
Strictly private and confidential
12

Strictly private and confidential
• Patients with HIV / AIDS, breast cancer and other diseases protested drug prices for life saving therapies and wanted speed in regulatory reviews.
• They also confronted firms about their pricing policies.
These have resulted in promolgumation of “ Orphan Drug Act ” of 1983 and new regulations that speed regulatory approval of drugs in 1990 ’s, especially that those of life saving drugs such as HIV/AIDS and Cancer.
• In 1984 “ Drug Price Competition and Patent Terms Restorative Act ” (Hatch-
Waxman) authorized US FDA to approve generics without additional preclinical or clinical testing.
• This has resulted in initiating generic business by large firms. They also purchased generic firms to expand their international business.
• Further, developing countries such as India and China took advantage of Hatch-
Waxman act and made their appearance globally by offering generic drugs at much cheaper price compared to U.S. and European companies.
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Strictly private and confidential
• In 1972, multinational companies controlled 70% of the domestic pharmaceutical market.
• Of the leading 50 pharma companies, 33 were foreign
• Now, the national sector occupies the leading position with 38 Indian companies in the top 50 and controlling 80% of the market.
• From Rs.10 crores in 1947 and Rs.360 crores in 1972, it has crossed 100,000 crores
(~1.2% of the world pharma market)
• Pharma exports crossed Rs.60,000 crores as against Rs.200 crores in 1972.
• All this was possible due to the efforts of the indigenous pharma companies
• Indian companies built up an enviable reputation for producing good quality drugs at affordable prices.
4

Strictly private and confidential
• The present API market in the world: $ 113 Billion.
• It is very competitive as there are more than 2000 firms and they have 5000 manufacturing sites.
• Cipla is one of the first companies to fully develop and manufacture APIs and laid foundation for the pharmaceutical industry. In India they manufacture 200 generic
API and reaching more than 170 countries world wide.
• Dr.
Reddy’s is another leading API manufacturer (60 APIs).
• Ranbaxy produces 100 APIs and present in 65 countries.
• Aurobindo manufacture 200 APIs and exporting to 200 countries.
• Sun Pharma manufacture 200 APIs at nine different places located in Hungary,
Israel and the U.S.
15

Strictly private and confidential
th
16

Strictly private and confidential
A case study for eliminating toxic substances
NH
2
N
O
CN
N-(4-Cyanophenyl)-3(S)-aminopyrrolidone
(Avra's first project: initiated in 1996)
UREA DERIVATIVES
(Anti Thrombiotic Agents)
US Patent: 5484946 (1996)
Filed June 1995
17

Unit-1 (2000)
R&D Centre, Nacharam, Hyderabad
Strictly private and confidential
Pilot plant
18

Strictly private and confidential
For medical abortion (Avra’s First Commercial Product)
Me
2
N
Me OH
H
H
O
RU-486
Sune Bergström
• RU 486 is a synthetic steroid used as an abortifacient in the first two months of pregnancy and in small doses as an emergency contraceptive.
• The drug was initially made available in France and other countries followed – often amid controversy
• RU 486 was discovered as a progesterone receptor antagonist.
• US FDA approved in 28 th September, 2000.
• Avra commercialised RU 486 in 2003 and exclusively supplied to Zydus Cadila for formulating and marketing in India.
19

Strictly private and confidential
Unit-2 (2005)
Nacharam, Hyderabad
Fine Chemical Block
20

Strictly private and confidential
N N
O
O
A
O
B
N
C
N
D
HO
E
O
O
Irinotecan [CPT-(II)]
(Trade name: Camptosar)
• Irinotecan is one of a number of analoges developed to circumvent the undesired properties of CPT - (I)
• Irinotecan functions as the soluble prodrug for the active metabolite SN - 38.
21

Strictly private and confidential
A
B
N
C
N
D
O
E
O
HO
O
Camptothecin
CPT - (I)
1. H
2
O
2
, AcOH
2. hv, dioxane, H
2
SO
4
(~ 40%)
HO
H
2
O
2
, FeSO
4
C
2
H
5
CHO aq.H
2
SO
4
(70%)
N
N
O
HO
O
O
7-Ethyl Camptothecin
N
N
O
HO
O
O
SN-38
N
Pyridine
N COCl
IRINOTECAN yield 20% from CPT-(I)
SAWADA.et.al., Chem. Pharm: Bull. 1991 , 1446.
22

Strictly private and confidential
HO
O
NH
2
AHPP
O
N
O
S-Trione
OH
O
O
N
HO
N
O
O
A
O
B
N
N
C
D
HO
E
O
O
Irinotecan
N
O
N
HO
O
O
SN-38
23

Unit-3 (2010), Visakhapatnam
Strictly private and confidential
24

Strictly private and confidential
• India joined WTO and accepted TRIPS Mandate
• Indian Patent Act 2005 was passed through an ordinance effective from 1 st
January 2005
• Product Patents allowed for all sectors
• Patentability of Inventions
• Licenses of Right Deleted
• Micro organisms to be made patentable
• Compulsory licenses for domestic use as well for export against third party licenses
• Pre and Post-Grant opposition provisions included
25

Strictly private and confidential
1.
Drugs with Incremental changes not worthy of exclusive rights .
Ex: Indian supreme court did not permit the validity of patent of Novatis Anti-Cancer drug, “ GLIVEC ” (Imatinib) as it has improved version and not a new invention.
However this drug received patents in 38 countries.
2.
Compulsory licensing for Anti-Cancer Drugs:
India issued its first compulsory licensing in March 2012, when Natco Pharma won the right to manufacture Bayer AG’s Anti-Cancer Drug, “ NEXAVAR” .
Recently Inida’s health ministry recommended for compulsory licensing of three anticancer drugs.
Trastuzumab (Breast cancer), Ixabepilone and Dasatinib (Leukamia). If this is accepted, these products will be available at a fraction of original price.
26

Strictly private and confidential
• Japan’s Eisai Pharma is expected to launch in
India, its novel anti-cancer drug Eribulin, sold under the brand name of Halaven . It is used in the treatment of third line metastatic Breast
Cancer.
• The company has divided patients in to three catagories: a) The lower income group will get the drug free.
b) The middle income patients will be eligible for discount on the full price.
c) The rich patients will be asked to pay full price.
• India’s Oncology market is estimated to be close to Rs.700 crores and growing at
20%. It is estimated to touch Rs.3000 crores by 2017.
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Strictly private and confidential
• WHO Global T.B. report of 2012 indicates that T.B. kills one person every two minutes in
India and 750 people every day.
• It is a very serious disease and annually ~ 3,30,000 Indian die due to the T.B.
• In the world, an estimated 8.6 million people developed T.B. 1.3 million died.
• Dr. Wadia (Hinduja Hospital) was the first to describe totally drug resistant T.B. from
India, building up to a new sense of urgency.
Br
• India is the World’s largest T.B. drugs producing countries and marketing.
All the four major drugs (Etambutol,
Rifampicin, INH, Pyrazinamide) are manufactured by Lupin
(Mumbai).
N
N
OH
• No new T.B. drug was developed for almost four decades after discovery of Rifampicin.
O
• Recently Johnson & Johnson discovered, Bedaquiline (US
FDA Approved) for MDR T.B. Drug.
Bedaquiline
28

Strictly private and confidential
• As per the World Health Organisation, 219
Million cases of Malaria were reported, resulting in about 800,000 deaths.
90% of which occurred in Africa.
This is the main cause of death for children under five, claiming every 45 seconds.
• Although Malaria is preventable and treatable, life saving drugs do not always reach the patients.
and
• Ranbaxy had launched the country’s first indigenously developed Anti-Malarial Drug
Synriam against Plasmodium Vivax, a strain responsible for almost half of Malaria infections in the World.
• Synriam (3 tablets Rs.130/- is a three day course) - It is a mixture of Arterolane Maleate and Piperaquine Phosphate.
Synriam
29

Strictly private and confidential
Ex: Polypill: New concept development by DRL, Hyderabad.
• Polypill contains Aspirin, Cholesterol lowering and Blood Pressure lowering drugs.
• The recent study involving a 1000 patients from India and a 1000 from Europe
(UK, Ireland and Netherlands) were randomly assigned either the Polypill or their normal combination of Medicines.
• The Polypill group had lower Blood Pressure and Cholesterol measurements.
• Heart disease is a leading cause of premature death and disability in India and is growing at Epidemic proportions.
• The Late Dr. Anji Reddy was keen to provide an affordable convenient treatment package to patients in India and elsewhere.
30

Strictly private and confidential
• It ranks 3 rd in terms of volume of products with 10% global share and 14 th largest by value (1.5%). This is because drug prices are lower in India to the extent of
25-50% compared to developed countries
• The country has more then 100 manufacturing facilities approved by US FDA.
The US FDA official figures indicate that 6300 active Drug Master Files (DMFs) with the regulatory body, of which 26% or 1,700 are from Indian companies
Avra
• The country has also a major share in the Abbreviated New Drug applications
(ANDS) filled with US FDA for marketing generic products
• Indian API manufacturing industry moves forward (average growth of 19% during the last 5 years) to meet the world’s need for high quality products at competitive prices.
31

Strictly private and confidential
1971
– Socialist India
2011 – A Flourishing market economy
1970-1971 1990-1991
GDP:
(Rs. Lakh Crores)
Per Capita Income:
(at constant prices)
Forex Reserves:
Exports:
FDI
Number of Passenger cars
Pay Cheques:
(Cabinet secretary’s monthly salary)
Rs.4.7
Rs.8,091
$ 0.97 bn
$ 2.1 bn
-
36,032
Rs.4,000
Rs.10.8
Rs.11,535
5.8
18.0
$ 0.13 bn
0.18 mn
Rs.30,000
2010-2011
Rs.48.8
Rs.41,129
274.0
254.0
30.3
2.9 mn
Rs.90,000
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Strictly private and confidential
India
Indian Men
Indian Women
World Wide
1950
40 years
2000
61
60
62
66
2010
65
63
66
68
• Today India has nearly 117 Million people over 60 years
• This is because of amazing progress in Medical & Biological Research
• Major challenges are:
New life style aliments such as Heart diseases, Hypertension, Cancers and Diabetes.
These are major cause of all deaths by 2030 (75%)
33

Strictly private and confidential
“Surely, Science is not merely an individual’s search for truth. It is something infinitely more than that ……. It must have a social objective before it.
”
Pandit Jawaharlal Nehru (1947)
“My idea of better ordered world is one in which medical discoveries would be free of patents and there would no profiteering from Life or Death”
Indira Gandhi
At WHO, Geneva, 1981
34

Strictly private and confidential
Council of Scientific and Industrial Research
All the three DG’s of CSIR (1985 – 95)
And three directors of NCL (1960 – 85)
All My Ph.D. Students and Colleagues
From NCL & IICT
K Venkataraman
Former Director,
National Chemical Laboratory
Dr. Y. K. Hamied
Chairman, Cipla Limited
35
E J Corey
Professor of Chemistry
Harvard University, USA
1990 Nobel Prize for Chemistry