3.0 Analysis of India’s Bulk Drug Registrations...
Transcript of 3.0 Analysis of India’s Bulk Drug Registrations...
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CHAPTER 3
3.0 Analysis of India’s Bulk Drug Registrations &Formulation Approvals with U.S.FDA
3.1 ANALYSIS OF INDIA’S STATUS IN BULK DRUG
REGISTRATIONS
The DMF Database provided by Center for Drug Evaluation and
Research (CDER) of U.S.FDA was retrieved and Type II DMFs which are
active as on 24 October 2011 have been analyzed to study India’s status in
bulk drug registrations. The analysis has been carried out for type II active
DMFs for its number, molecules and therapeutic categories.
3.1.1 Number of Type II Active DMF Registrations
From the analysis of the data available in CDER as on 24 October
2011, it is observed that a total of 7,652 Drug Master Files (DMFs) filed
starting since 1956 are still active (or being renewed periodically) with it.
These DMFs have been filed for approximately 2,276 drug substances
(APIs), Intermediates, materials used in them or for drug products of
innovator formulations and were filed by 1,857 companies from 53
countries. The complete details of the number of holder companies
belonging to different countries along with the number of type II active DMF
filings with U.S.FDA as on 24 October 2011 is provided in Table 3.1.
Table 3.1: Total Number of Type II Active DMFs filed with U.S.FDA ason 24 Oct 2011
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Data Source: U.S.FDA DMF Database
Confidential
India is the leader in terms of number of filings and number of
companies filing on Indian facilities. The number of type II active DMFs
filed along with number of holder companies for top 10 countries are
depicted in Figure 3.1. The top 10 countries accounted for 84.54% of all
DMFs filed with U.S.FDA. India is the holder of largest number of DMFs
with 2667 followed by United States (1183) and China (720). It is second to
USA in number of molecules. As on 24 October 2011, the country has 2667
DMFs (34.85%) for 632 (27.77%) molecules filed by 340 companies
(18.39%).
Figure 3.1: Total Number of Type II Active DMFs filed with U.S.FDAalong with number of holder companies for top 10 countries (as on 24
Oct 2011).
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Data Source: U.S.FDA DMF Database
3.1.2 Yearly growth rate in Type II Active DMF Filings
Analysis of year wise type II DMF filings with U.S.FDA has been
carried out on the data provided in U.S.FDA DMF Database. It is observed
that the first DMF was filed from India in the year 1972 and is currently
owned by Dr. Reddy’s Laboratories. Another DMF is filed by the same
company after six years in 1978. A year later third DMF is filed by Franco
Indian Pharmaceutical Company. However, filings began in earnest only
since 1986 and the country has not looked back since then.
India experienced a rapid growth in number of DMFs during the last
10 years, especially so between the past six years from 2004 to 2010.
There are only 104 active DMFs that were filed from India during a span of
28 years prior to the year 2000. Since that year, the number increased
exponentially from 33 active DMFs in 2000 to 351 in 2010. Nearly, 84.36%
of all the current active DMFs have been filed during the last 10 years with
more than two third of them during the last 6 years alone (Table 3.2).
Table 3.2: Year wise Cumulative Number of DMFs filings of India withU.S.FDA from 1972 to 2010
(Data Source: U.S.FDA DMF Database)
Year
No. of DMF filings
from India
Cumulative
No. of DMFs
of India
1972 1 1
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1973 - 1
1974 - 1
1975 - 1
1976 - 1
1977 - 1
1978 1 2
1979 1 3
1980 - 3
1981 - 3
1982 - 3
1983 - 3
1984 - 3
1985 - 3
1986 3 6
1987 3 9
1988 4 13
1989 5 18
1990 1 19
1991 5 24
1992 2 26
1993 7 33
1994 1 34
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1995 4 38
1996 6 44
1997 17 61
1998 20 81
1999 23 104
2000 33 137
2001 43 180
2002 59 239
2003 103 342
2004 164 506
2005 247 753
2006 277 1030
2007 309 1339
2008 350 1689
2009 347 2036
2010 351 2387
Year wise comparison of type II active DMF filings of India with 5
other top filers (USA, Italy, China, Japan and ROW) was made from the
data retrieved from DMF Database and tabulated in Table 3.3. The same
comparison has been presented in Figure 3.2. India is the top filer during
2004 to 24 October 2011.
Table 3.3: Yearly number of Type II active DMFs filed by top Countrieswith U.S.FDA as on 24 Oct 2011
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Data Source: U.S.FDA DMF Database
Confidential
Figure 3.2: Yearly number of Type II active DMFs filed by topCountries with U.S.FDA as on 24 Oct 2011
Data Source: U.S.FDA DMF Database
3.1.3 Company and Country Competition
Country wise analysis of Type II active DMFs filed with U.S.FDA for
the data available on 24 October 2011 has been carried out to study
company and country-wise competition. It is observed that over 18% of the
companies having DMFs with U.S.FDA are on Indian facilities. Eight of the
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top 10 companies that filed DMFs, are from India. Among Indian
companies, Aurobindo ranks first followed by Matrix and Dr.Reddy’s. The
list of top 10 companies having type II active DMFs with U.S.FDA as on 24
October 2011 is tabulated in Table 3.4.
Table 3.4: Top companies having Type II Active DMFs with U.S.FDAData Source: U.S.FDA DMF Database;
Rank Company CountryNo. of Type - II
Active DMFs
%
Share
1 Teva Group Israel 200 2.61
2 Aurobindo Pharma Ltd India 147 1.92
3 Matrix Laboratories Limited India 157 2.05
4 Dr Reddys Laboratories Ltd India 136 1.78
5 Cadila Pharmaceuticals Ltd India 131 1.71
6 Cipla Ltd India 123 1.61
7 Lupin Ltd India 108 1.41
8 Ranbaxy Lab Ltd India 100 1.31
9Sun Pharmaceutical
Industries LtdIndia 98 1.28
10 Mallinckrodt Chemical Inc USA 75 0.98
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3.1.4 Molecules wise DMFs filings
Further analysis of molecules for which DMFs were filed as on 24
October 2011 using the DMF Database provided by U.S.FDA is carried out.
The analysis reveals that out of total 632 molecules filed by India, there are
four or more DMFs in 193 molecules (30.54%). For example for
Atorvastatin, out of the total 37 DMFs filed with U.S.FDA by all countries,
India alone accounts for 26 DMFs. The list of molecules having 15 or more
than 15 type II active DMFs as on 24 October 2011 is provided in Table
3.5.
Table 3.5: List of molecules having 15 or more than 15 type II activeDMFs active from India
Data Source: U.S.FDA DMF Database
Sl.No. Subject No.of DMFs
1 Citalopram hydrobromide 15
2 Esomeprazole magnesium 15
3 Lansoprazole 15
4 Montelukast sodium 15
5 Olanzapine 15
6 Ondansetron 15
7 Rabeprazole sodium 15
8 Rivastigmine 15
9 Rizatriptan Benzoate 15
10 Zolpidem tartrate 15
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11 Carvedilol 16
12 Efavirenz 16
13 Lamivudine 16
14 Lamotrigine 16
15 Levetiricetam 16
16 Sertraline hydrochloride 16
17 Sumatriptan 16
18 Valsartan 16
19 Duloxetine hydrochlororide 17
20 Escitalopram oxalate 17
21 Amlodipine bisulfate 18
22 Aripiprazole 18
23 Donepezil hCl 18
24 Omeprazole 18
25 Irbesartan 19
26 Metoprolol succinate 19
27 Pioglitazone hydrochloride 19
28 Telmisartan 19
29 Losartan potassium 21
30 Pantoprazole sodium 21
31 Cefuroxime axetil 23
32 Venlafaxine hydrochloride 24
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33 Quetiapine fumarate 25
34 Clopidogrel bisulfate 26
35 Risedronate sodium 26
36 Atorvastatin 26
Similarly, over 80% of the DMFs in several top molecules such as
Clopidogrel, Lamivudine, Sertraline, Ramipril, Sildenafil, Zidovudine,
Fluvastatin, Tadalafil, Citalopram, etc., are filed from Indian facilities. This
implies that the country is vying for top molecules. For 137 molecules like
Esomeprazole, Escitalopram, Celecoxib, Lopinavir, Naratriptan, Salmeterol,
Tenofovir, etc., only India has filed DMFs.
3.1.5 Therapeutic Category wise DMF filings
An examination of therapeutic categories of molecules for their number
of DMFs reveals that India is strong in Anti-hypertensive, Anti-HIV, Anti-
diabetic, GI Tract, Anti-virals, Anti-infectives, etc. However, the country is
absent mostly in fermentation products, controlled substances and
steroids. For example, India does not have any DMFs for several important
fermentation products such as Penicillin G, Clavulanate, Fludarabine,
Heparin, Acarbose, etc., controlled substances like Morphine, Fentanyl,
Amphetamine, Propoxyphene, Codeine, Dronabinol, Hydromorphone, etc.
and corticosteroids like Cortisone, Hydrocortisone, Fludrocortisone,
Predinisone, Methyl prednisolone.
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3.3 Analysis of India’s Status in Formulations Approvals with
U.S.FDA
The list of all pharmaceutical products approved till 28 December
2010 by U.S.FDA were identified from Drug@fda, Electronic Orange Book
and National Drug Code Directory (NDC Database) by studying approval
history, letters, reviews and other related documents. A comprehensive
analysis is then carried out on this data to study India’s strengths in
product approvals. Product Approvals were studied for New drugs (NDA –
New Drug Application), Biological (BLA – Biological Licensing Application),
Generics (ANDA – Abbreviated New Drug Application) and New molecules
(NME – New Molecular Entity). Using the data, analysis has been carried
out for all types of above said product registrations in various categories
such as prescription, OTC, discontinued and tentative approvals.
3.2.1 NUMBER OF PRODUCT APPROVALS OF U.S.FDA
From the analysis of product approvals granted by CDER as on 28
December 2010, it is observed that, of the total 26,232 product approvals
granted, 43% (11,327) were discontinued and only 57% (14,905) are still
active (Table 3.6 & Figure 3.3). Out of these total, active pharmaceutical
product approvals (14,905), 91% (13,555) are prescription products while
4% (531) are OTC products and the remaining are tentative approvals
(Figure 3.4, Table 3.6).
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Figure 3.3% Share of Product Approvals
with U.S.FDA
Figure. 3.4% Share of Active ANDAs
with U.S.FDA (As on 28 Dec 2010)Data Source: Orange Book
Table 3.6………(3 pages)
Confidential
There are 1,255 prescription products and 11 OTC products which areolder than 29 years (approved prior to 1982) still being marketed in USA(Table 3.7).
Table 3.7: Number of Product Approvals granted by U.S.FDA prior to1982
Data Source: Electronic Orange Book, NDC Directory, Drugs@FDA
S.No.Country
Product
Approval Prescription Discontinued OTC Tentative
Grand
Total
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1 USA
BLA 1 ₋ ₋ ₋ 1Generic 316 1946 ₋ ₋ 2262
NDA 393 888 10 ₋ 1291NME 203 374 ₋ ₋ 577
2 IndiaGeneric 1 3 ₋ ₋ 4
NDA 2 1 ₋ ₋ 33 Israel
Generic 34 195 ₋ ₋ 225NDA 5 12 ₋ ₋ 93NME 2 11 ₋ ₋ 13
4 Switzerland
Generic 55 151 ₋ ₋ 206NDA 33 96 ₋ ₋ 129NME 14 83 ₋ ₋ 97
5 Canada
Generic 2 9 ₋ ₋ 11NDA ₋ 3 ₋ ₋ 3NME 5 ₋ ₋ ₋ 5
6 UK
Generic 2 86 ₋ ₋ 88NDA 9 113 ₋ ₋ 122NME 16 62 ₋ ₋ 78
7 Germany
Generic 1 29 ₋ ₋ 30NDA 41 77 1 ₋ 119NME 2 11 ₋ ₋ 13
8 Japan Generic 2 12 ₋ ₋ 14
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NDA 9 5 ₋ ₋ 14NME 3 7 ₋ ₋ 10
9 Iceland
Generic 9 3 ₋ ₋ 12NDA 1 ₋ ₋ ₋ 1NME ₋ ₋ ₋ ₋ ₋
10 Ireland
Generic 1 4 ₋ ₋ 5NDA 17 31 ₋ ₋ 48NME 2 5 ₋ ₋ 7
11 France
Generic 4 22 ₋ ₋ 26NDA 12 34 ₋ ₋ 46NME 12 42 ₋ ₋ 54
12 Belgium
Generic 5 59 ₋ ₋ 64NDA ₋ 13 ₋ ₋ 13NME 5 3 ₋ ₋ 8
13 Italy
Generic 3 2 ₋ ₋ 5NDA 8 32 ₋ ₋ 40NME 2 5 ₋ ₋ 7
14 Denmark
Generic 1 8 ₋ ₋ 9NDA 3 20 ₋ ₋ 23NME 7 8 ₋ ₋ 15
15 Sweden Generic 3 ₋ ₋ ₋ 3
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NDA 3 2 ₋ ₋ 5NME 2 1 ₋ ₋ 3
16 Puerto Rico Generic 4 7 ₋ ₋ 1117 Australia Generic - 2 ₋ ₋ 218 Greece Generic - 6 ₋ ₋ 619 Singapore Generic - 2 ₋ ₋ 2
20
Website
not
Available
Generic ₋ 250 ₋ ₋ 250NDA ₋ 97 ₋ ₋ 97NME ₋ 12 ₋ ₋ 12
21 Poland Generic ₋ 1 ₋ ₋ 122 Armenia Generic ₋ 1 ₋ ₋ 1
Grand Total 1255 4846 11 0 6184
Since 1982, the number of yearly approvals granted which averaged
212 per year increased to nearly 884 per year (five year average for the year
between 2006-2010). This shows the rapidity of increasing competition
from generic prescription products in U.S. markets.
3.2.1.1 NUMBER OF GENERIC DRUG APPROVALS OF INDIA
India has been experiencing a spurt in generic registrations across
the world (Table 3.8). Analysis of India’s generic approvals with U.S.FDA
reveals that the country has emerged among the top countries in its
regulatory approvals granted. Analysis of India’s approvals in various top
stringent regulated countries and semi regulated countries using the online
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databases provided by respective countries also has been carried out. The
analysis reveals that India stands first in number of approvals granted by
EDQM, by number of valid CEPs. Nearly one out every four valid CEPs
granted are to India, or by the number of molecules (31.88%) or companies
(18.84%). The country stands first in Ethiopia accounting for over 17% of
approvals and also in Tanzania with 39.32% of all market authorizations
granted by that country. Similarly, India has strong presence in CIS
countries, South Africa, etc. The country has majority of qualifications
granted by global procuring agency World Health Organisation (WHO).
Table 3.8: Regulatory Compliance status of India with variousRegulatory Authorities of the World
Data source: U.S.FDA DMF Database, Orange Book & NDC Database
EDQM Online Database
UK MHRA Online Database
DACA Ethiopia Online Database
TFDA Online Database
Azerbaijan Regulatory website
CDSCO website
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Confidential
3.2.1.2 Yearly Growth Rate of India’s Prescription Generic drug
Approvals
India is currently experiencing a boom in generic drug approvals.
India’s number of approvals for generic prescription products (ANDA
approvals excluding OTC, discontinued and tentative approvals) with
U.S.FDA have grown tremendously during the last six years from 2005 to
2010 with 1363 approvals compared with meager 171 approvals it has
prior to it. Year wise number and % share of India and four other top
countries in prescription generic product approvals granted by U.S.FDA is
presented in Table 3.9.
Table 3.9: Year wise % share of India, USA, Israel and Switzerland inPrescription Generics Approvals granted by U.S.FDA
Data Source: Electronic Orange Book, NDC Directory
Year
PrescriptionGener
icWorld
PrescriptionGener
icIndia
%Share
ofIndia
inPrescriptionGener
icprodu
ct
PrescriptionGener
icUSA
%Share
ofUSAin
PrescriptionGener
icprodu
ct
PrescriptionGener
icIsrael
%Share
ofIsrael
inPrescriptionGener
icprodu
ct
PrescriptionGeneric of
Switzerland
%Share
ofSwitzer
landin
Prescription
Generic
product
P-1982*
443 1 0.23% 31671.33
% 347.67
% 5512.42%
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1982 60 4
6.67% 42
70.00% 7
11.67% 0
0.00%
1983 65 3
4.62% 48
73.85% 3
4.62% 2
3.08%
1984 78 5
6.41% 48
61.54% 14
17.95% 5
6.41%
1985 103 4
3.88% 75
72.82% 13
12.62% 2
1.94%
1986 155 2
1.29% 124
80.00% 11
7.10% 9
5.81%
1987 205 6
2.93% 131
63.90% 16
7.80% 14
6.83%
1988 187 1
0.53% 134
71.66% 13
6.95% 27
14.44%
1989 60 0
0.00% 47
78.33% 9
15.00% 2
3.33%
1990 2 0
0.00% 1
50.00% 0
0.00% 0
0.00%
1991 86 5
5.81% 69
80.23% 6
6.98% 5
5.81%
1992 93 1
1.08% 58
62.37% 24
25.81% 6
6.45%
1993 134 0
0.00% 84
62.69% 22
16.42% 13
9.70%
1994 111 2
1.80% 81
72.97% 18
16.22% 8
7.21%
1995 167 0
0.00% 91
54.49% 42
25.15% 23
13.77%
1996 200 3
1.50% 111
55.50% 45
22.50% 31
15.50%
1997 269 12
4.46% 160
59.48% 52
19.33% 22
8.18%
1998 232 7
3.02% 133
57.33% 35
15.09% 20
8.62%
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1999 185 3
1.62% 110
59.46% 35
18.92% 3
1.62%
2000 317 6
1.89% 163
51.42% 50
15.77% 33
10.41%
2001 327 42
12.84% 156
47.71% 55
16.82% 19
5.81%
2002 524 12
2.29% 242
46.18% 105
20.04% 51
9.73%
2003 384 19
4.95% 192
50.00% 59
15.36% 24
6.25%
2004 582 33
5.67% 301
51.72% 105
18.04% 21
3.61%
2005 562 90
16.01% 256
45.55% 86
15.30% 49
8.72%
2006 653 142
21.75% 312
47.78% 69
10.57% 35
5.36%
2007 930 256
27.53% 419
45.05% 90
9.68% 35
3.76%
2008 954 299
31.34% 430
45.07% 77
8.07% 34
3.56%
2009 926 290
31.32% 383
41.36% 73
7.88% 71
7.67%
2010 958 286
29.85% 385
40.19% 69
7.20% 64
6.68%
*P-1982: Prior to 1982
Comparison of % share of yearly prescription generic product
approvals granted to India and 3 other top countries (USA, Israel and
Switzerland) from 1991 to 2010 provided in Table 3.9 is presented in Figure
3.5.
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Figure 3.5: Changing scenario of Prescription Generic productapprovals (1991 to 2010)Data Source: Electronic Orange Book, NDC Directory
3.2.1.8 Country wise Pharmaceutical Product Approvals
Country wise analysis of pharmaceutical product approvals granted
by U.S.FDA for biological, new drugs, generic drugs, and new molecular
entities has been carried out for the data available in Orange Book as on 28
December 2010. India accounts for 12.24% of all approvals (prescription,
OTC and tentative) and is second to USA which has a share of 53.61% of all
approvals in that country. Also only 27 Indian companies hold these
ANDAs compared with 211 companies from USA. It has products for 35.4%
of all molecules. India is closely followed by Israel, Switzerland and Canada
in that order. Of the total 37 countries having active product approvals in
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USA, top 10 countries account for 93.68%. (Figure 3.6, 3.7, 3.8, 3.9 and
Table 3.10).
India accounts for 11.32% and 9.23% in prescription generics and
OTC approvals respectively and country stands second next to USA. Israel
(9.30%), Switzerland (7.32%) and Canada (3.04%) occupy 3rd, 4th and 5th
positions in active prescription product approvals. It has very low share in
number of discontinued products given that files majorly generic products.
The growing presence of India in U.S.FDA is attested by the fact that it
competes with in number of Tentative Approvals being granted to the
country. Currently, it accounts for 15.47% of the prescription and OTC
generic products approvals.
Figure 3.6:% Share of Top 10Countries in Prescription Product
Approvals
Figure 3.7:% Share of Top 10 Countriesin OTC Product Approvals
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Figure 3.8:% Share of Top 10Countries I
Tentative Product Approvals
3.9:% Share of Top 10 Countriesin Discontinued Product Approvals
Table 3.10: % Share of All Countries in all Pharmaceutical ProductApprovals [Biological Licensing
Applications (BLA), Generic drug, New Drug Application (NDA), NewMolecular Entity (NME)] in
Prescription, OTC, Tentative and Discontinued Products
Data Source: Electronic Orange Book, NDC Directory, Drugs@FDA
Confidential
3.2.1.4 Country wise Company Approvals of ANDAs
Out of total companies that have been granted approvals in generics
(prescription and OTC) belonging to 27 countries, India has second largest
number of companies (27) though second to USA (211) (Table 3.11). The
top 5 companies among them are very aggressive. A few other top Indian
generic companies in domestic market and in exports have not yet entered
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into U.S. markets. Besides, several foreign companies hold ANDA approvals
on Indian facilities both for innovator as well as generics which are taken
into consideration. From the above, it must be noted that the present
research does not include 265 prescription & OTC generic products
belonging to erstwhile Indian companies of Ranbaxy, Matrix, Dabur
Oncology and Minrad (subsidiary of Piramal Healthcare) which now belong
to foreign acquirer companies but include 90 approvals held by Indian
subsidiaries abroad.
Currently there is only one Indian company out of the top 10 generic
companies of the world, though most of them have their manufacturing
units in India. This clearly demonstrates India’s strengths in generic
formulations and there are good chances of more companies from India
would be among top 10 generic companies of the world.
Table 3.11: Number of Active Companies from different countries &their product basket with U.S.FDA
Data Source: Orange Book & NDC Directory
Confidential
Analysis of company-wise approvals reveals that in prescription
generics, Teva is the leader with 623 products followed by Mylan and
Watson. The top 16 companies account for more than 50% of the total
prescription generic product approvals among which two companies viz.,
Aurobindo (9th position) and Dr. Reddy’s (16th position) are from India.
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Among the total 60 companies that have product approvals in OTC sector,
Perrigo with a share of 21·75% is the leader followed by Watson Labs and
Dr. Reddy’s.
In spite of India’s regulatory strengths in various markets, currently
there is only one Indian company which appears in the list of top 10
generic companies of the world by total pharmaceutical sales in 2010. The
list of top 25 generic companies along with their product approvals were
tabulated in Table 3.12.
Table 3.12: Top 25 Companies with Generic Drug Product Approvalswith U.S.FDA
Data Source: Electronic Orange Book & NDC Directory
Confidential
As on the date of analysis, Aurobindo Pharma which is previously
known as bulk drug manufacturing also stands first in number of product
approvals granted extending the company’s position from bulk drugs to
formulations. It is followed by Dr. Reddy’s, Zydus Group, Sun Pharma,
Wockhardt and Lupin Pharma (Table 3.13)
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Table 3.13: Number of Indian Companies & their Product approvalBasket with U.S.FDA
Data Source: Electronic Orange Book & NDC Directory
Confidential
3.2.1.5 Therapeutic category wise Product Approvals granted by
U.S.FDA
Therapeutic category wise analysis of total pharmaceutical product
approvals granted by U.S.FDA has been carried out to study India’s status
in various therapeutic categories. Highest number of product approvals
was granted in the Anti infective category which has a share of 14.52%. It
is followed by CNS (14.04%), Cardiovascular (9.65%), Corticosteroids
(7.14%) and Diagnostics (6.34%) (Figure 3.10).
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Figure 3.10: Therapeutic category Wise Share of All PharmaceuticalProduct Approvals Granted by U.S.FDA
Data Source: Orange Book, NDC Directory
Therapeutic Category Wise Analysis of Prescription, OTC, Tentative
and Discontinued Approvals Granted by U.S.FDA
Most number of prescription approvals is for CNS (24%) and
Respiratory (17%). Anti infective stands third with a share of 13% followed
by corticosteroids (6%) (Figure 3.11).
Among OTC product approvals granted by U.S.FDA, GI Tract (21%),
Analgesic and Anti inflammatory (19%) occupy 1st and 2nd positions,
whereas Anti infective (16%) and CNS (10%) occupy 3rd and 4th positions
respectively (Figure 3.11).
Analysis of Tentative approvals granted by U.S.FDA revealed that
more than one third of tentative approvals were granted in CNS (36%)
category. This is followed by Cardiovascular (17%), Anti HIV (14%), Anti
cancer (8%) and Anti infective (7%) and Anti diabetic (6%) categories. A
relatively less number of tentative approvals were granted in GIT,
Metabolic, Anti Viral and Respiratory categories (Figure 3.11).
Majority of the discontinued approvals were in CNS (21%), CVS (13%)
and anti-infective categories (Figure 3.11, Table 3.14).
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Figure 3.11: Therapeutic category wise share of all generic approvals(Prescription, OTC, Tentative and Discontinued) granted by U.S.FDA
Data Source: Orange Book, NDC Directory
% Share in Prescription productApprovals
% Share in OTC product Approvals
% Share in Tentative Approvals % Share in Discontinued productApprovals
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Table 3.14: % Share in Prescription, OTC, Tentative, Discontinuedproduct approvals
Data Source: Orange Book, NDC Directory
Confidential
3.2.1.5.1 Therapeutic category wise analysis of product approvals of
USA
Therapeutic category wise analysis of all pharmaceutical product
approvals granted by U.S.FDA were analyzed and presented in Figure 3.13.
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Figure 3.13: % Share of Therapeutic category wise Generic DrugApprovals of
Data Source: Orange Book, NDC Directory
Table 3.15: % Share in Prescription, OTC, Tentative and Discontinuedproduct Approvals of
Data Source: Orange Book, NDC Directory
Confidential
3.2.1.5.2 Therapeutic Category wise analysis of product approvals of
India
India’s approvals are broadly in synchrony with the approval
therapy-wise approval trends in U.S.FDA. The country also has highest
number of approvals in CNS category (35%), cardiovascular (20%), anti
infectives (16%) and GI tract (6%). It is comparatively stronger in number
of approvals in anti retrovirals, anti microbials, CVS, anti-diabetics and
dermatological. However, it is poor in Corticosteroids, Anti-cancer and
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diagnostics (Figure 3.14,Table 3.16). Further examination reveals the
country is weak in Biotechnology products including fermentation
products, complex chemistry, advanced dosage formulations and specialty
formulations.
Figure 3.14: Therapeutic category wise Approvals of IndiaData Source: Orange Book, NDC Directory
Table 3.16: % Share in Prescription, OTC, Tentative and Discontinuedproduct Approvals of India
Data Source: Orange Book, NDC Directory
Confidential
It may be noted that the top therapy categories are not necessarily
have top market shares. The market value is determined by sales value of
number of innovator molecules in the category. As per the IMS Health
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report of 2010, it is reported that in U.S., Oncologics is top therapy by
value occupying US$22.3bn. of the market respectively.91 Respiratory
agents, Lipid Regulators are the other top therapies in 2010. However,
Attention Deficit Hyperactivity Disorder (ADHD), HIV antivirals and
Angiotensin II blockers tops the list in growing therapies. The IMS Report
on top therapeutic categories in U.S. in 2010 is presented in Figure 3.15.
Figure 3.15: Top Therapy Category's of USA by Value and their CAGR(2006-2010) (US$ bn.& %)
Source: IMS Health, 201087
3.2.1.6 Molecule wise India’s Presence in Prescription GenericsAnalysis of the molecule-wise prescription approvals granted by
U.S.FDA using the data provided by orange book as on 28 December 2010,
it is observed that out of total molecules having prescription ANDAs, India
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is present only in 14% of the molecules. Further, analysis indicates that in
twelve molecules such as Cefipime hydrochloride, Cefixime, Desloratadine,
Dexchlorpheniramine Maleate, Brompheniramine Maleate,
Dextromethorphan hydrobromide, Pseudoephedrine, Enflurane,
Promethazine hydrochloride, Codeine phosphate, Amifostine, and Lithium
Carbonate only India has prescription ANDAs. At the same time it has more
than 50% share in product approvals of several anti retrovirals (ARVs) and
antibiotics such as Zidovudine, Rivastigmine, Stavudine, Didanosine,
Cefotaxime, Ciprofloxacin, and Cefepime. A comparision of the India’s
status in approvals of prescription generic molecules for the top 25
molecules are tabulated in Table 3.17.
Table 3.17: India’s status in approval wise Prescription genericmolecules
Data Source: Orange Book, NDC Directory
Confidential
It is observed that, in several other molecules having more than 20
prescription approvals such as Diltiazem HCL, Gentamicin Sulfate,
Amitriptyline HCL, Lorazepam, Clonazepam, Diazepam, Acyclovir, Fentanyl,
Morphine, Theophyline, Meperidine HCL, India does not have any
approvals. Several of these molecules pertain to corticosteroids, controlled
substances and fermentation based products (Table 3.18).
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Table 3.18: Approval wise Top Generic Prescription products in whichIndia is absent
Data Source: Orange Book, NDC Directory
Rank in
all
molecul
es
Active
Ingredient
Broad
TherapeuticUSA
Indi
aIsrael
Grand
Total (All
countries)
12Diltiazem
HydrochlorideCardiovascular 44 0 6 71
22Gentamicin
Sulfate
Anti Infective
(Fermentation
based product)
37 0 2 54
28
Acetaminophe
n; Oxycodone
Hydrochloride
CNS (controlled
substance)39 0 1 49
33 LorazepamCNS (controlled
substance)34 0 3 46
40Sotalol
HydrochlorideCardiovascular 26 0 7 44
50Doxazosin
MesylateCardiovascular 20 0 8 40
56Hydrocortison
eCorticosteroid 26 0 6 38
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59 ClonazepamCNS (controlled
substance)20 0 8 37
61Amitriptyline
HydrochlorideCardiovascular 29 0 - 35
71Meperidine
Hydrochloride
CNS (controlled
substance)26 0 2 33
75 Doxycycline
Anti Infective
(fermentation
based product)
20 0 1 32
79 Cimetidine Anti Infective 15 0 8 31
91Morphine
Sulfate
CNS (controlled
substance)23 0 - 28
93 Acyclovir Anti Viral 11 0 6 27
96Epirubicin
HydrochlorideAnti Cancer 17 0 2 26
97
Amphetamine
Aspartate;
Amphetamine
Sulfate;
Dextroamphet
amine
Saccharate;
CNS (controlled
substance)4 0 11 26
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Dextroamphet
amine Sulfate
99Phentermine
HydrochlorideCNS 11 0 5 26
102 Fentanyl
Analgesic &
Anti-
Inflammatory
(controlled
substance)
9 0 4 25
104 DiazepamCNS (controlled
substance)16 0 6 25
107 TheophyllineRespiratory
(NTI)20 0 24
3.2.1.7 Dosage form wise India’s Presence in Product Approvals
India’s strength in various dosage forms has been analyzed for the
data available as on 28 December 2010. For the purpose of analysis, all the
dosage types have been classified into three broad categories, namely
advanced, non conventional and conventional formulations. Advanced
formulation consists of controlled release products, implants, patches,
depot preparation and inhalations and so on. Non conventional dosage
forms include products meant for rectal, vaginal and urethral routes.
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Conventional dosage forms include oral, topical and injectables which are
self explanatory.
Study of products approved from India reveals that 83 per cent are
oral, mostly conventional tablets (690) and capsules (137). India has very
little presence in advanced formulations accounting for just 14 per cent of
its total products. India is also completely absent from nonconventional
dosage form (Table 3.19).
Table 3.19: Dosage form wise approvals in Prescription, OTC,Tentative & Discontinued products
Data Source: Drugs@FDA, Orange Book, NDC Directory
Confidential
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3.3 Emerging Opportunities for India in Global Pharmaceutical Market
It has been observed that patents of several innovator molecules
whose sales are between US$723mn. to US$12.73bn. are expiring in the
coming five years. Atorvastatin, Montelukast Sodium, Esomeprazole
Magnesium, etc. are among the top molecules whose patents are expiring.
The opportunity from these top 50 molecules alone is valued at
US$63.85bn. even if their sales are assumed to remain same as in 2009.
Of this 80% market value will erode after patent expiry which implies that
the market or generics is valued at US$12.77bn. Generic companies can
potentially capture 20-30% of this market estimated at US$2.55-3.83bn.
(Table 3.20).
Table 3.20: Selected Block Buster Drugs going Off Patent in differentTherapeutic Category
Data Source: Orange Book & Drugs@FDA
Confidential
3.3.1Emerging Opportunities for India in U.S. PharmaceuticalMarketA complete list of Molecule wise USA Patent & Exclusivity Expiry
Analysis is attached in Appendix I.
3.3.2Therapeutic Category wise Molecule opportunities
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Therapeutic category wise penetration of generics in total number of
molecules is analyzed using the data provided in Orange Book, Drugs@FDA
as on 28 December 2010. The % share of molecules whose drug patent as
well as product patent expired and no generics are filed but are still active
as on 28 December 2010 are given in Table 3.18. Analysis indicates that
generic companies only target molecules having large number of molecules
in that therapeutic category. Penetration is strong in CVS, Analgesics,
Antiviral and CNS products. Generic penetration is week in Electrolyte
Replenishers, Nutritional Supplements, Diagnostics, etc. An analysis
based on the % share of generics and % share of molecules where generics
are not available and whose patent will be expiring, further penetration is
possible in CNS, Renal and Oncology categories (Table 3.21).
Table 3.21: Therapeutic category wise Molecule Opportunity withU.S.FDA
Data Source: Orange Book, Drugs@FDA, NDC Directory
Confidential
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3.4 WARNING LETTERS ISSUED
Analysis of number of warning letters issued by U.S.FDA to
companies belonging to various countries during 1996 to October 2011 has
been carried out using the data available in U.S.FDA website. Examination
of number of warning letters issued by U.S.FDA indicates that Indian
companies have been issued very few warning letters compared to the
number of approvals as compared to USA (326) and China (19) and others
(Figure 3.15). In spite of the fact that India’s only recent emergence as top
filer in USA (1996 to October 2011), only 18 warning letters have been
issued so far indicating strong compliance capability of the country (Figure
3.16,Table 3.22).
Figure 3.16: Issue of U.S.FDA Warning Letters to different Countries(1996 to Oct 2011)
Data Source: U.S.FDA website
Year wise analysis of total number of warning letters issued by
U.S.FDA is carried out and presented in Figure 3.17. Also a comparison of
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total number of warning letters received by India, USA and China is done
and the same is tabulated in Table 3.22.
Figure 3.17: Year wise total number of Warning Letters issued byU.S.FDA
Data Source: U.S.FDA websiteTable 3.22: Year wise number of Warning letters issued to three
countriesData Source: U.S.FDA website
Year wiseNo. of Warning letters
USA India China
1996 1 0 0
1997 12 0 0
1998 8 0 1
1999 15 1 0
2000 6 1 4
2001 0 1 0
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2002 79 2 0
2003 4 0 0
2004 1 0 2
2005 22 0 0
2006 15 2 0
2007 40 0 0
2008 33 2 1
2009 34 1 2
2010 30 6 6
Oct-11 26 2 3
Total 326 18 19
Reasons for all warning letter issued to Indian companies are
presented in Table 3.23. Analysis indicates that out of 18 warning letters,
four were issued to API companies while the rest were for formulations.
Out of the 18 warning letters 12 were for cGMP deviations while two were
due to accord of new drug substance status.
Table 3.23: Total number of Warning Letters Issued to IndianCompanies with the Reasons
Data Source: U.S.FDA website data
S.
NoCompanies Year Reason for Warning letter
1 Claris 2010 Finished Pharmaceutical/Unapproved New
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Lifesciences
Limited
Drugs/Adulterated
2 Synbiotics Ltd 2010 CGMP for Deviations/Adulterated
3
CP
Pharmaceutica
ls, Ltd. 2010
CGMP for Finished
Pharmaceuticals/Adulterated
4Choksi
Laboratory 2010
CGMP for Finished
Pharmaceuticals/Adulterated
5
Stericon
Pharma Pvt.
Ltd. 2010
CGMP for Finished
Pharmaceuticals/Adulterated
6Shreeji Homeo
Clinic 2010
Unapproved/Uncleared/Unauthorized
Products Related to the H1N1 Flu Virus
7Yag Mag Labs
Private Limited 2011
CGMP for Finished
Pharmaceuticals/Adulterated
8
Cadila
Healthcare
Limited 2011
CGMP/Finished
Pharmaceuticals/Adulterated
9 Lupin Limited 2009CGMP for Finished
Pharmaceuticals/Deviations/Adulterated
10Ranbaxy
Laboratories,2008 CGMP/Drug/Deviations/Adulterated
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Ltd., Dewas,
India
11
Ranbaxy
Laboratories,
Ltd., Ponta
Sahib, India
2008 CGMP/Drug/Deviations/Adulterated
12
Ranbaxy
Laboratories
Limited
2006Current Good Manufacturing Practices for
Finished Pharmaceuticals/Adulterated
13 Wockhardt Ltd 2006
Current Good Manufacturing
Practices/Active Pharmaceuticals
Ingredient/Adulterated
14
Ranbaxy
Pharmaceutica
ls Inc.
2002
Certain Drugs Accord New Drug Status
through Rulemaking
Procedures/Guaifenesin
15
M G
Acquisition
LLC
2002
Certain Drugs Accorded New Drug Status
through Rulemaking
Procedures/Guaifenesin
16Granules India
Limited2001
Active Pharmaceutical Ingredient
Manufacturing Facility/Adulterated
17
SOLPharmaceuticals Limited (Dr.Reddy)
2000 Good Manufacturing Practices for ActivePharmaceutical Ingredient
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18 FDC Ltd. 1999 Active Pharmaceutical Ingredient
3.5 OPPORTUNITIES IN PARAGRAPH IV CHALLENGES
Relying solely on commodity generics may no longer be seen as a
viable option, leaving companies no choice but to target niche products,
among them biologics, or by picking up for development those drugs
dropped by innovators for clinical or commercial reasons.
Bioequivalent generic versions of drugs that are not protected by
patents can be produced and marketed in the U.S. by any company,
subject to FDA approval. However, a generic company may obtain FDA
approval before patent expiry if it certifies its product does not infringe the
listed patents or the patents are invalid (paragraph IV certification). Patent
holders may then sue the ANDA filer for patent infringement. If the patent
holder sues the ANDA filer within 45 days of notification, the FDA may not
approve the ANDA for 30 months from the date of notification. If no suit is
filed within 45 days, the FDA may approve the ANDA at any time.
180-DAY EXCLUSIVITY
In order to encourage generic companies to develop non-infringing
products and challenge invalid patents, the Hatch- Waxman act provides
the incentive of 180 days of market exclusivity for the first company to file
an ANDA with paragraph IV certification for a product. The FDA may not
approve additional ANDAs for a period of 180 days commencing from the
first commercial marketing of the first-to-file product. In cases where more
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than one ANDA with Paragraph IV certification is filed on the same day, the
period of exclusivity may be shared.
Analysis of Para IV challenges filed by various companies in USA
during the last 5 year period indicates that Teva continued to be by far the
most prolific filer of ANDAs with patent challenges of 161 products. Mylan
has stayed in second place with links to patent challenges on 108 different
products; Novartis occupying third place challenged 97 products. Four
Indian companies viz., Ranbaxy (Daiichi), Sun, Dr. Reddy’s and Lupin find
place among the top 10 challengers. (Figure 3.18). It indicates the growing
skills in patents domain and confidence in Indian companies.
Figure 3.18: Companies with the Patent Challenges on record as onJune 201188
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3.6 ANALYSIS OF INDIA’S PHARMACEUTICAL BILATERAL
TRADE
Analysis of Bilateral trade of India, both pharmaceutical exports and
imports has been carried out using HS codes classification to identify the
commodity type. Initially the data provided by DGCI&S is extracted from a
package known as “India Trades” provided by a private agency, CMIE.
Using this data, HS codes classification, each commodity is identified and
analysis has been performed to derive the category wise, country wise and
region wise exports and imports.
Research on India’s HS Codes revealed that the country’s trade in
pharmaceuticals sector is actually higher than the current understanding.
India’s total exports of drugs, pharmaceutical and fine chemicals in the
year 2010-11 stood at approximately US$13,233·12mn. and including
medical equipment and surgical, the figure stands at US$13,831·28mn.
much higher than the officially estimated figure of US$10,393.54mn. The
sector grew to a compounded annual growth rate (CAGR) of 15.1% during
the five year period from 2006-07 to 2010-11. The imports are approx. at
US$10,778·33mn. during the same period including imports of medical
devices and surgicals which are valued at US$13831.28mn. The country
thus had a positive trade balance of US$3,052·95mn. in this sector. India
exports to 201 countries and territories of the world during 2010-11.
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3.6.1 Category wise Exports of India’s Pharmaceuticals
Composition of exports of India’s pharmaceuticals has been analysed
using the HS Codes. The analysis revealed that formulation exports
including biologicals occupy approximately 34% of the country’s exports
followed by fine chemicals (28%), bulk drugs (23%), herbals (6%), medical &
diagnostic equipment and surgical with a share of 3% and 2% respectively.
Both excipients and medical devices are estimated to have a share of 1%
(Figure 3.19).
Figure 3.19: % Share of India’s Pharmaceutical sector ExportsData Source: DGCI&S Data
3.6.2 Category wise Imports of India’s Pharmaceuticals
Majority of the imports of India are fine chemicals with a share of
69% followed by bulk drugs (19%), medical & diagnostic equipment
intermediates and excipients at 19%, Medical & diagnostic equipment at
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8%. Formulations along with biologicals at 9% and surgical at 4%
respectively. The percentage share of each category of India’s
Pharmaceuticals imports are presented in Figure 3.20.
Figure 3.20: % Share of India’s Pharmaceutical Sector ImportsData Source: DGCI&S Data
3.6.3 Region wise share of India’s Pharmaceutical Imports andExports.
3.6.3.1 Region wise share of India’s Pharmaceutical Imports
Analysis of the India’s pharmaceutical imports from the data
provided by DGCI&S, Ministry of Commerce and Industry revealed that
Asia is the largest sourcing region for imports followed by European Union
(18%). Asean and Middle East regions occupy an equal share of 14% in
India’s imports of drugs, pharmaceuticals & fine chemicals. North America
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has a share of 10%, other European countries and Africa collectively
occupy a share of 5% respectively (Figure 3.21,Table 3.24).
Table 3.24 : Region wise share of India’s Import of Pharmaceuticals(2006-07 to 2010-11) (figs. in US $ mn., %)
Data Source: DGCI&S Data
Confidential
Figure 3.21: Region wise share of India’s Imports of Drugs,Pharmaceuticals & Fine chemicals, 2010-11(figs. in %)
Data Source: DGCI&S Data3.6.3.2 Region wise share of India’s Pharmaceutical Exports
Analysis of India’s exports of pharmaceuticals revealed that North
America is the largest export destination of India’s pharmaceuticals
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(excluding Medical devices and fine chemicals) followed by Europe and
Africa. Middle East, Asean, Latin American Countries (LAC), CIS Countries,
Asia and South Asia region occupy the 4th, 5th, 6th and 7th position in
India’s pharmaceutical exports. (Figure 3.22,Table 3.25). The details of
calculation involved in the derivation of region wise share of India’s
Pharmaceutical exports are presented in Appendix II.
Figure 3.22: Region wise share of India’s Exports of Drugs,Pharmaceuticals & Fine Chemicals 2010-11 (figs. in US $ mn., %)
Data Source: DGCI&S DataTable 3.25: Region wise share of India’s Exports of India’s Drugs,
Pharmaceuticals & Fine Chemicals (2006-07 to 2010-11) (figs. in US $mn., %)
Data Source: DGCI&S Data
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Confidential
For bulk drugs & intermediates, North America is the most important
destination with exports over US$2.5bn. and the region is also among the
important destinations for India’s formulations. An estimated 52·36% on
the exports to the region are bulk drugs & intermediates followed by
formulations with a share of 44·38%. North America is followed by EU
which is an important destination for formulations, biologicals as well as
bulk drugs & intermediates. Africa is another most important destination
for India’s formulation exports valued at nearly US$1.7bn. growing at a five
year CAGR of 22%. Exports of bulk drugs & intermediates, biologicals and
excipients are also growing at very high CAGRs to this region. The country
majorly exports formulations to CIS region. In Asia, the major importers of
bulk drugs & intermediates from India are China, Israel, Turkey, S. Korea,
and Thailand and nearly two thirds to LAC region.India’s exports potential
to Oceania region is largely untapped as evident from the country’s share
compared with market size of the region.
India’s Exports to USA
India’s exports to USA based on statistics provided by U.S.
Government in US Trade Stat Express have been analyzed from 1989 to
2010. India’s rank in total imports (bulk drugs and formulation) of USA,
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year wise number of exports of bulk drugs and formulation, its share in
U.S. imports and yearly cumulative number of DMFs and ANDA approvals
were presented in Table 3.26.
The analysis indicates that the country’s bulk drug exports have
started growing during the last 15 years. However, the exports crossed
US$100mn. only since 2001. During the five years from 2006 to 2010 the
country’s exports have increased nearly three to four times with growth
respect to number of DMFs. During 2010, it exported over 1% of bulk drug
to USA making it 18th largest country behind Spain, Sweden and
Singapore.
Table 3.26: India’s Rank in Bulk drugs and Formulations Exports 1989to 2010) (figs. in US $ mn., %)
Data Source: DGCI&S Data
Confidential
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Figure 3.23: % Share of India’s Exports of Bulk drugs andPharmaceutical products to USA (figs. in US$ mn).
Source: US Trade Stat Express (SITC 541 & SITC 542)
However, India is 10th largest formulation exporting country with a
share of 4.66% and 18th largest bulk drug exporting country. Considering
the number of filings, molecules going off patents and country’s growing
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strength in drug registrations, increasing filings of foreign company DMFs
on Indian facilities leading to growth in contract manufacturing
opportunities, during last 5 years, it can be concluded that India’s exports
would continue to grow. Given the cost advantage offered by Indian
facilities and growth dependency on sourcing from India, foreign MNCs
would increase their M & A (Mergers and Acquisitions) activities.
Figure 3.24: India’s Bulk Drug and Formulation Exports to USA (figs.in US $ mn.,)
Source: US Trade Stat Express (SITC 541 & SITC 542)