Transcript View PPT - Indian Drug Manufacturers` Association

Strictly private and confidential
Taking Innovations to the Market –
A Scientist’s Journey
A V RAMA RAO
Avra Laboratories Pvt. Ltd.
Hyderabad, INDIA
Golden Jubilee Celebrations of “Indian Drugs”
Mumbai
Saturday, 8th March, 2014
1
Strictly private and confidential
The need for Self Reliance
• 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.
2
Strictly private and confidential
Indian Patent System
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
Production of Diazepam
Original process of HOFFMAN-LA-ROCHE:
(USP. 3109843, dated 5-11-1963)
H
N SO2
NH2
1. BzCl
NH2
O
Cl
PTS - Cl
Cl
O
Cl
ZnCl2,
2.Hydrolysis
CH3
Base
( 40% )
Me
N
Me
NH
MeI
Base, Hydrolysis
1. ClCH2COCl
O
Cl
N
Cl
2. Hexamine
DIAZEPAM
NCL Process:
NO2
PhCH2CN
NaOH
O
Cl
Me
N
Me
NH
N
Cl
O
Me2SO4
Fe,H
Cl
O
Cl
O
N
DIAZEPAM
Commercialized by Cipla in 1973
4
Strictly private and confidential
Extraction of Natural Products
Vinca Alkaloids
(Vinblastine and Vincristine)
OH
N
CH3
Avra
H
N
HO
CH3
N
H
O
O
N
CH3
H
R HO
O
VINBLASTINE: R=Me
VINCRISTINE: R=CHO
5
CH3
CH3
O
O
O
CH3
Strictly private and confidential
Ibuprofen
(Anti Inflammatory, Anti Rheumatic)
BOOTS Process (GB 971 700:2.2.1961):
O
O
H3C O
CH3COCl
Cl CH2CO2Et
AlCl3
NaOEt,EtOH
OEt
CH3
1.NaOH
CHO
2. H
(B)
(A)
CH3
CH3
N
NH2OH 1/2 H2SO4
OH
CH3
CN
CO2H
NaOH
(D)
Cheminor’s Approach:
NaCN
O
CH3
CH3
OH
H2,Raney-Ni
(B)
(C)
6
CH3
SOCl2
Cl
Strictly private and confidential
Vitamin B6: NCL Process
•
Initiated in 1959; prevailing price $ 460/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)
aimed to bring down to $ 350/kg
O
N
O
X
O
X
HO
O
CO2H
CO2H
N
Substituted Pyridines
Merck Process: NCL approach (1965 - 73)
H2N
CH3
H2N
EtOH
CO2H
HCl
P2o5
N
OHC
CH3
OEt
O
O
H3C
1. 180 °C
2. HCl
H
N
CH3
CO2Et
CO2Et.HCl
O
1960, Price $80/kg
1965, Price $55/kg
1970, Price $30/kg
H2N CHO
CH3
HO
CH2OH
CH2OH
N
.HCl
Project failed - RM price was higher than the prevailing
market price
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Strictly private and confidential
Vitamin B6: NCL Process 1980-83
(Based on Roche approach)
SO2Cl2
CH3COCH2CO2Et
N
O
H2N CHO
CH3COCHClCO2Et
N
CH3
NH3
O
CO2Et
O
O
N
CH3
P2O5
CO2NH2
O
O
CN
HCl
HO
180 °C
HO
H3C
H3C
N
Technology was implemented by Lupin in 1985
8
CH3
O
CH2OH
CH2OH
N
.HCl
Strictly private and confidential
AIDS and HIV
AIDS (Acquired Immunodeficiency Syndrome), is caused by
infection with Human Immunodeficiency Virus (HIV).
O
HN
O
HO
Twenty years ago, an AID Diagnosis was equivalent to a death
sentence. The introduction of AZT, First AIDS drug in 1987 offered
hope.
N
O
N3
AZT
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
AZT
Production of AZT
O
O
HN
O
O
HO
N
1. PhOCO2Ph
2. NaHCO3
N
3. DMF
O
1. Br2
O
2. H2, Pd/C
O
HO
HO OH
HN
N
O
O
HN
1. LiN3
2. H+
N
O
HO
O
HO
N3
HO
HO
N
O
Avra
Beta-Thymidine
Rama Rao's approach:
O
O
O
HO
O
N
HN
N
O
OH
OH
AZT
1. Raney Ni, H2
2. NaOMe, MeOH
1. PhOCO2Ph
2. NaHCO3
3. DMF, 150o C
HN
1. Ac2O, Py
N
O
2. HBr
O
HO
O
AcO
N
O
OAc Br
HO
J. C. S. Chem. Commun., 1994, 1255
US Patent No. 5596087 (Jan 1997)
10
HIV/AIDS Drugs: Indian Contribution
•
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
Strictly private and confidential
Strictly private and confidential
HIV Drugs: at Affordable Price
•
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 (~ 1/40th 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.
12
Strictly private and confidential
New Policy Challenges of U.S. Pharma Companies
•
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” (HatchWaxman) 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 HatchWaxman act and made their appearance globally by offering generic drugs at much
cheaper price compared to U.S. and European companies.
13
Strictly private and confidential
Indian Drug Industry – Post 1972 Patent Era
•
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
Active Pharmaceutical Ingredients (APIs)
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
Avra Laboratories Pvt. Ltd.,
Founded on 15th August, 1995.
Mainly devoted to R&D Projects, Custom Synthesis & Manufacture
16
Strictly private and confidential
G.D. Searle Project
A case study for eliminating toxic substances
NH2
N
O
UREA DERIVATIVES
(Anti Thrombiotic Agents)
US Patent: 5484946 (1996)
Filed June 1995
CN
N-(4-Cyanophenyl)-3(S)-aminopyrrolidone
(Avra's first project: initiated in 1996)
17
Strictly private and confidential
Avra Laboratories Pvt. Ltd.,
Pilot plant
Unit-1 (2000)
R&D Centre, Nacharam, Hyderabad
18
Strictly private and confidential
RU 486 (Mifepristone):
For medical abortion (Avra’s First Commercial Product)
Me2N
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 28th 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
Avra Laboratories Pvt. Ltd.,
Unit-2 (2005)
Nacharam, Hyderabad
Fine Chemical Block
20
Strictly private and confidential
Camptothecin and its Analogs
O
C
B
O
N
A
N
N
N
D
HO
E
O
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
Synthesis of Irinotecan from Camptothecin
O
A
B
N
CN
O
H2O2, FeSO4
D
HO
E O
N
O
C2H5CHO
aq.H2SO4
(70%)
O
N
HO
Camptothecin
CPT - (I)
O
7-Ethyl Camptothecin
O
1. H2O2, AcOH
2. hv, dioxane, H2SO4
N
N
HO
O
N
(~ 40%)
N COCl
IRINOTECAN
Pyridine
HO
O
yield 20% from CPT-(I)
SN-38
SAWADA.et.al., Chem. Pharm: Bull. 1991, 1446.
22
Strictly private and confidential
Avra’s Final Synthesis of Irinotecan and
its Key Intermediates
O
O
HO
O
NH2
AHPP
OH
O
N
N
O
O
N
HO
O
S-Trione
SN-38
O
C
O
N
HO
A
B
N
N
O
Irinotecan
23
N
D
HO
E
O
O
O
Strictly private and confidential
Avra Laboratories Pvt. Ltd.,
Unit-3 (2010), Visakhapatnam
24
Strictly private and confidential
Indian Patent Act – 2005
•
India joined WTO and accepted TRIPS Mandate
•
Indian Patent Act 2005 was passed through an ordinance effective from 1st
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
Post 2005 I.P. Issues
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
Health Benefit for All
•
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.
27
Tuberculosis (T.B.) – Major Killer in India
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).
•
No new T.B. drug was developed for almost four decades
after discovery of Rifampicin.
•
Recently Johnson & Johnson discovered, Bedaquiline (US
FDA Approved) for MDR T.B. Drug.
28
N
OH
N
O
Bedaquiline
Strictly private and confidential
Malaria: Major Threat to Developing Countries
•
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.
•
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.
29
Synriam
and
Strictly private and confidential
Affordable and Convenient Treatment for Patients
(Cardiovascular Disease)
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
Indian Pharmaceutical Industry – Current Status
• It ranks 3rd in terms of volume of products with 10% global share and 14th 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
How Indian Economy Changed
1971 – Socialist India
2011 – A Flourishing market economy
1970-1971
1990-1991
2010-2011
GDP:
(Rs. Lakh Crores)
Per Capita Income:
(at constant prices)
Rs.4.7
Rs.10.8
Rs.48.8
Rs.8,091
Rs.11,535
Rs.41,129
Forex Reserves:
$ 0.97 bn
5.8
274.0
Exports:
$ 2.1 bn
18.0
254.0
-
$ 0.13 bn
30.3
36,032
0.18 mn
2.9 mn
Rs.4,000
Rs.30,000
Rs.90,000
FDI
Number of Passenger
cars
Pay Cheques:
(Cabinet secretary’s
monthly salary)
32
Strictly private and confidential
Life Expectancy at Birth
1950
2000
2010
40 years
61
65
Indian Men
60
63
Indian Women
62
66
World Wide
66
68
India
• 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
Acknowledgement
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
E J Corey
Former Director,
National Chemical Laboratory
Professor of Chemistry
Harvard University, USA
1990 Nobel Prize for Chemistry
Dr. Y. K. Hamied
Chairman, Cipla Limited
35