Global Production, Regulatory, and Trade Environment Fortunak - Global... · 2. fumaric acid,...
Transcript of Global Production, Regulatory, and Trade Environment Fortunak - Global... · 2. fumaric acid,...
Global Production, Regulatory, and Trade Environment
Joseph [email protected]@Comcast.net
APIs and Finished Pharmaceutical Products (FPPs)
API Synthesis
N
N N
N
NH2
OH
N
N NH
N
NH2
28
R-propylene carbonate, (2)
KOH (10 mol%, DMF)
O O
O
29
HPA, 30
DESMP (4), THF, Mg(OtBu)2
not isolated
N
N N
N
NH2
OP OEt
O
OEt
TMSCl, NaBr, DMF
TsOP OEt
O
OEt
31
N
N N
N
NH2
OP OH
O
OH
321. CMIC (6), TEA, NMP
2. fumaric acid, 2-PrOH
N
N N
N
NH2
OP O
O
O
OO
O O
O
O
HOOCCOOH
TDF, 33PMPA
2
N
OOH
NH
OF
FO
O
OOH
CH3
several steps
N
OHOBn
OH
MeO2C
3
5 steps
4 OCH3
3 additional steps
N
OOH
NH
OF
FN
O
O
H1
Dolutegravir
17
OOEtEtO2C
18
OEtHO2C
19
OOEtOO
O
NH
F
F
20
OOEt
O
NH
F
F NH
OCH3
OCH3 21
OOEt
O
NH
F
F N
OCH3
OCH3
As per Scheme 4
12
N
OXRO2C
OX
DMF acetal
15
Dolutegravir
RO2C
13
OXRO2C
N
OMe
OMeCO2Me
MeO
OO
OMe
Amine
14
OXRO2C
NH
OMe
OMe
Base
X = Cl, OCH3, OBn
N
OXHOOC
OMe
OMeCO2Me
16
Dolutegravir61% over4 steps approximately 70% Y.
API and FPP pricingAPI FPP Pricing, US FPP Pricing , LMICs API pricing/kg,
India/ChinaGeneric API pricing PPPY or per treatment
Sofosbuvir $84,000 $200 - $650 $800 $27
Daclatasvir $63,000 $45 $850 $4.25
Tenofovir disoproxil fumarate (TDF)
$15,000 $66 $140 $15.40
Efavirenz $2,600 $48 $105 $24
Lamivudine (3TC) $42 $135 $15
TLE (TDF/3TC/EFV) $95 $95 $55
Imatinib $125,000 $140 <$40
Cyclophosphamide $27,000 $270 - $310 <$20
Cholic Acid $312,000 N/A $370/kg (MP Biomedical)
$33 - $57
0
100
200
300
400
500
600
700
800
900
2008 2009 2010 2011 2012 2013 2014 2015 2016 2017
TDF$/kg
PMPA $/kg
0.00
100.00
200.00
300.00
400.00
500.00
600.00
700.00
800.00
900.00
2008 2009 2010 2011 2012 2013 2014 2015Year
TDF raw material Cost factors ($/kg TDF) vs. API pricing, 2008-2015
Adenine
R-PC
DESMP
Mg t-buOx
CMIC
Sum
Processing (3 steps)
Model total
Drug
(indication)
Dose Pricing/dose, US Pricing /dose,
LMICs
Cefuroxime
(anti-infective)
500 mg, 20
count
$1.815 - $2.15 $0.368
Atazanavir
(AIDS)
300 mg, 30
count
$29.74 - $52.77 $0.5213
Atenolol
(cardiovascular)
50 mg/30
count
$0.133 - $0.3787 $0.0059
Atorvastatin
(lipid-lowering)
20 mg/30
count
$0.3327 - $2.933 $0.0714
Representative pricing of medicines in the US versus median pricing in LMICs.
Full Disclosure
Universal access to HIV treatment is one of the greatest success stories in medicine (>17 million treated).This should be repeated for mass treatment of Hepatitis B, C, and Cancer - and more quickly
Impact of Global Access Campaigns Upon the Indian and
Chinese Pharma Industries
Priorities in LMICs?
Causes of Death: USA, 2014All Causes 2,626,418Cardiovascular Diseases 614,348Malignant Neoplasms 591,699Chronic Lower Respiratory Diseases 147,101
Accidents 136,053
Cerebrovascular Disease 133,103Alzheimer’s Disease 93,541Diabetes Mellitus 76.448Influenza, pneumonia 55,227Nephritis 48,146Suicide 42,773
Global Burden of Disease report, Lancet 2014, 385: 117-17132
Causes of Death - Africa
• BUT: This does not even count the incalculable burden of cardiovascular diseases and diabetes…
• (Rob Ridley) Approximately 14 million deaths per year occur in sub-Saharan Africa because of preventable or easily treatable diseases:
• Diarrheal diseases• Simple Infections• Malaria• Tuberculosis• HIV/AIDS• Hepatitis B and C
Do we compare/contrast India and China?
Local Pharmaceutical Manufacturing - Africa
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ACADEMIA
CLASSROOMAND
LABORATORYTRAINING
INDUSTRY
Regulatory
• Pharma manufacturing requires skilled technicians, engineers, and scientists trained in pharmaceutical technology and production• “There is insufficient skilled labor to support the growing pharma industry… we spend
up to 6 months to train people but not enough people with basic skills are available
• Human resources must be developed in the areas of industrial pharmacy, production management, regulatory science, and quality control
Challenges of Pharmaceutical Manufacturing in Afreica
Foreign exchange
Availability of skilled labor force
Underdeveloped related and supporting industries
• Foreign exchange shortage causes significant challenges in importing machineries and raw materials necessary to support the pharmaceutical industry – “It can take up to 6-7 months to get approval for foreign currency and that is
discouraging... even though the pharmaceutical industry has preference, it is still one of the biggest issues facing our sector.”
• There is no production of APIs domestically; and nearly all raw materials must be imported
• Similarly, most primary packaging (e.g. PVC, bottles, vials, foils) must be imported• Bioequivalence study centers are just being established
Challenges of pharmaceutical manufacturing in Africa
Regulatory environment
• Lengthy regulatory policies for drug approvals have imposed access limitations• The current legal limitation of working with a maximum of three distributors was cited
as another regulatory barrier to the growth of the domestic pharmaceutical industry
Patents
The Patent Estate - Evergreening
• Pharmaceutical companies represent nearly every aspect of drug development and delivery as containing patentable innovation:
• Composition of matter • Method of use • Combinations with other drugs• Pharmaceutical compositions (formulations)• Processes and Intermediates (not listed in the Orange Book)• Crystalline forms (salts, polymorphs, hydrates, solvates, co-crystals,
dispersions)• Latter-day “improvements”
Tenofovir Alafenamide – Patent Applications
1998 2001 2003 (3) 2004 (3) 2006 2009 2010 2011 )2) 2012 2013 2014 (4) 2015 (3) 2016
Tenofovir, Tenofovir Disoproxil, Tenofovir Alafenamide
N
NN
N
NH2
O P
OO
O
O
O O
O
O
O
N
NN
N
NH2
O P
OHOH
O
Tenofovir disoproxil Tenofovir (API)
N
NN
N
NH2
O P
O
O
O
CO2iPr
First published by McGuigan et. al.,(1989) and appliedto hundreds of antiviral compounds
Synthesized by Antonin Holy and tested by Eric de ClerqProdrug selected by Gilead Sciences
(John Martin)
Sofosbuvir
Emerging Issues
• Alternative salts of tenofovir disoproxil fumarate (citrate, phosphate) from Indian generics have been approved by the EMA (March, 2017) and the tartrate is expected to be approved this month
• This provides a means for getting around originator patents, but it also creates new patent issues… (DTG, TDF, solvates and new crystal forms of important APIs (aripiprazole/abilify)
• Tenofovir disoproxil fumarate is presently taken by an estimated 12MM people in LMICs
• Patent coverage on the drug molecule theoretically expires in 2017/2018• Gilead Sciences seeking to extend this to 2020 in US and Europe with a 2015
application covering solid state forms of tenofovir disoproxil, preventing generic companies from