Apr 7, 2014 - i, DMSO, ClCOCOCl, CH2Cl2, Et3N; ii,MeNO2, KF, Me2CHOH; iii, Ac2O, Et2O, DMAP; iv, NaBH4, EtOH; v, H2, Pd/C or Ra-Ni i. 85-95 %.
CHALLENGES IN GENERIC API DEVELOPMENT FROM THE CHEMIST‘S PERSPECTIVE
Stanislav Rádl
OUR COUNTRIES
Poland Czech Republic Germany
Estonia Latvia
United Kingdom France
Lithuania
Portugal
Slovakia Kazakhstan
Hungary
Russia Cyprus Turkey Switzerland Ukraine Italy
Bulgaria
Slovenia
Romania
Albania
Challenges in generic API development
Zentiva is the 3rd largest and fastest growing generics company in Europe. Zentiva is made of 6500 employees.
Greece
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Zentiva operates in 32 countries and reaches out to a target population of approx. 800 million people.
2
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CONTENT
1. Introduction
2. Case Study I - Statins
3. Case Study II - Sartans
4. Conclusions
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1. Introduction
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DISCOVERY AND DEVELOPMENT OF A NEW DRUG
Launch Clinic Development Get the Candidate Get the Lead Get the Screen Get the Idea April 7th, 2014
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HISTORY OF GENERIC DRUGS
1983 Drug Price Competition and Patent Term Restoration Act = HatchWaxman Act
●
Drugs launched from 1984 – standard 20 yrs patent protection
●
Drugs launched after 1962 – ANDA (Abbreviated New Drug Application) bioequivalence
●
> 1000 Applications within a year
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LEGISLATIVE REQUIREMENTS
● Patent protection o 20 years o + up to 5 years of SPC (Supplementary Protection Certificate)
● Data Exclusivity - EU – registration of a generic drug is allowed after 6 (10) years after registration in the country
● From 2004 8 + 2 + 1 rule o 8 years after 1st registration in EU – registration o additional 2 years – production o additional 1 year - significant clinical benefit
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DATA AND MARKET EXCLUSIVITY OF A NEW DRUG
T TY E K IVI R A US M L C X E
DATA EXCLUSIVITY
Original Drugs
8 years
2 yrs
Generics Reference Product Market Authorization Application
1 yr
Generics Launch
Extra Market Exclusivity can be added if a new indication is registered in 8 first years
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A T Y R T KE IT X E AR SIV M LU C X E
REQUIREMENTS FOR GENERIC DRUGS EU – ESSENTIAL SIMILARITY
● Identical API (Active Pharmaceutical Ingredient), excipients may vary ● Identical in strength, dosage form and route of administration ● Reference product must be marketed in the country (ina county for EU) ● Only original drug can serve as a reference product ● Identical indication as the reference product ● Bioequivalent with the original drug ● Identical or very similar specification as the original drug (identical impurity profile)
● Manufactured under GMP (Good Manufacturing Practice)
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BIOEQUIVALENCE STUDIES
● The only clinical study required for ANDA is bioequivalence study ● The study is done in healthy volunteers as a two-way crossover study
● The generic drug must be bioequivalent with the reference original drug
● There are 3 principal pharmacokinetic parameters evaluated o Area Under the Curve (AUC) o Maximum plasma concentration (cmax) o Time of the maximum plasma concentration (tmax)
● All of these parameters are statistically processed and should be within the acceptance limits (90 %)
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BIOEQUIVALENCE STUDIES
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LIMITS OF IMPURITIES AND DEGRADATION PRODUCTS
Max. DD
Disregard limit
Unknown impurity
Known impurity
≤2g
0.05 %
0.10 % or 1.0 mg
0.15 % or 1.0 mg
> 2g
0.03 %
0.05 %
0.05 %
● Identification limit for most APIs is 0.10 % ● Qualification limit for most APIs is 0.15 % ● For impurities over the QL, the safety must be proved by: o Toxicological study o For generics by proving that the original drug has a similar impurity profile
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CHANGES IN PATENT SITUATION - EVERGREENING
● Prolongation of patent protection (evergreening) o New processess o New salts, polymorphs and pseudopolymorphs o New galenic forms o New use
● Real patent situation is not known, mainly due to the patent activities of generic companies
● As a consequence, the generic API development must start ASAP, usually during the Phase III clinical studies of the original drug
● Attrition rate is involved
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2. Case Study I Statins
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FULLY SYNTHETIC STATINS F
F
OH
OH OH
OH
CO2 Ca
CO 2Na N
N
i-Pr
Pitavastatin
Fluvastatin
F F OH
OH CO 2Ca1/2
N
OH i-Pr
CO2C
N HN
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O
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Me
17
N
N SO 2Me
OH
i-Pr
ATORVASTATIN F
OH
OH
O
N
O
-
Ca2+ HN
O
2
● Polymorphism - > 50 crystalline forms described, form I x amorphous
● Chemical purity ● Chiral purity ● Stability – chemical, chiral, polymorphic April 7th, 2014
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PATENT SITUATION
● Process patents by Warner-Lambert (Pfizer): o EP 244 364; EP 247 633; EP 330 172; EP 409 281 o US 4 611 067; US 4 681 893; US 5 003 080; US 5 097 045; US 5 103 024; US 5 124 482; US 5 149 837; US 5 155 121; US 5 155 251; US 5 216 174; US 5 245 047; US 5 248 793; US 5 273 995; US 5 280 126; US 5 342 952; US 5 397 792; US 5 686 104; US 5 969 156; US 6 121 461
o WO 2002/055519; WO 2005/0145039; WO 2006/097909
● In SciFinder – 167 process patents for atorvastatin (2009)
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PATENT SITUATION
● General patent by Warner-Lambert EP 247,633 (Priority 1986) o Structure generally claimed o Acid, lactone and salts claimed o Disadvantageous process, cis-racemate o Nothing about polymorphism F
F
F
OH Ph
Ph
O O
N
Ph
O COOMe
N
O
O O
O
NHPh
NHPh
NHPh
F
F
OH
OH
H Ph
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N
Challenges in generic API development O
O
20 NHPh
O
Ph
N
O NHPh
OH COOMe
PATENT SITUATION
● Specific patent by Warner-Lambert EP 409,281 (Priority 1989) o Structure specifically claimed o Acid, lactone and salts claimed o Disadvantageous process to the R,R isomer o Nothing about polymorphism Mg
F -
O
F
2+
F
Ph O
-
O Ph
OH
Ph Ph
Ph
N
OH COOMe
N
O NHPh
NHPh
COOt-Bu
N
O O
O
Ph
O
NHPh
F
F
OH
OH
OH
H Ph
N
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N
O
O
O
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Ph O
NHPh 21
NHPh
COOt-Bu
PATENT SITUATION
● Specific patent by Warner-Lambert US 155,251 (Priority 1991) o Convergent synthesis o Nothing about polymorphism
NaCN EtOH, H2O
OH O Br
OEt
MeCOOt-Bu, LDA THF, - 50 °C
OH O NC
OH O
O
NC
OEt
Ot-Bu
Et2BOMe, NaBH4 MeOH, -97 °C
O
O
NC
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Me2C(OMe)2 aceton
O
OH OH O NC
Ot-Bu
22
Ot-Bu
PATENT SITUATION
● Specific patents by Warner-Lambert EP 848,704 and EP 848,705 (Priority 1995)
o Polymorphs I and III claimed o ‚Amorphous atorvastatin is obtained using the original procedures‘
● Formulation patent Warner-Lambert EP 680,320 (Priority 1993) o Stabilized composition containing basic inorganic salts of Ca, Mg or Li, …
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PATENT SITUATION
Basic patent: Particular molecule : Real process: Formulation Real polymorph:
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Priority 30.5.1986 Priority 21.7.1989 Priority 1.10.1991 Priority 19.1.1993 Priority 17.7.1995
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2011 2013 2015
PATENT SITUATION
● Actavis Patent WO 2008/096377 (Priority 2007) o List of 5 degradation products (without synthesis) o 15 Claims covering stable formulations containing ATV and at least 1 of the mentioned impurities
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ZENTIVA ATORVASTATIN PROJECT Facts o o o
Basic patent and relevant process patents are not valid in CE Atorvastatin with amorphous API or own crystalline form could be launched in most CE in 2005 (data exclusivity) The same product could be launched in WE in 2011 without using inorganic bases in the formulation (x form I in 2015)
Decision To develop atorvastatin amorphous (> 10 crystalline forms were known) o To develop own process for the atorvastatin amorphous API without isolating any crystals o
Risks Atorvastatin was known to be chemically unstable o Amorphous APIs are known to be less stable than crystaline ones o Amorphous APIs are known to be more soluble – different formulation should be developod for bioequivalency o Polymorphic stability of amorphous atorvastatin was not known o
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ATORVASTATIN SYNTHESIS – ZENTIVA
O OH
i, ii, iii O 91 %
O NC
O
OH
70 %
90 %
I
ix
O
iv
O
O NC
O I
75-80 %
v
O
O
vi or vii,viii
O CHO
65 -70 %
O
NC
i, BuLi/THF; ii, CO2 ; iii, I2; iv, p-TsOH,aceton, r.t.; v, KCN/DMSO, 40 oC; vi, OsO4 -NaIO4 /dioxan-H2 O; vii, O3 ; viii, Me 2S; x, CrO3 -H 2SO 4/aceton, 0 oC;
S. Rádl, J. Stach: Tetrahedron Lett. 43 2087-2090 (2002).
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ATORVASTATIN SYNTHESIS – ZENTIVA
i
O
O
CO2t-Bu
HO
85-95 %
ii
O
O O
CO 2t-Bu
95 %
O
O
CO 2t -Bu
O2N OH
90 %
iii
O
v
O CO2t -Bu
H 2N
100 %
O O2N
iv
O CO2t -Bu
85-92 %
CO 2t-Bu
O 2N Me
O O
i, DMSO, ClCOCOCl, CH2Cl2, Et3N; ii,MeNO2, KF, Me2CHOH; iii, Ac2O, Et2O, DMAP; iv, NaBH4, EtOH; v, H2, Pd/C or Ra-Ni
S. Rádl: Synth. Commun. 33, 2275-2283 (2003).
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O
O
28
ATORVASTATIN SYNTHESIS – WL PROCEDURE
F
F
O
N
HN
OH
O
O
O
OH
O
N
HCl, THF
HN
O
O
O
1. NaOH 2. HCl F
F
OH OH H N
O
N
O ∆
HN
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HN
O
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O
OH
O OH
ATORVASTATIN SYNTHESIS – ZENTIVA PROCEDURE
F
F
F O
O
N
HN
OH
O O
N
HCl, THF
HN
O
O
OH
O
OH
O
OH
O ONa
N
NaOH
+ HCl
HN
O
+ NaCl + NaOH
1. heptane extraction 2. ethyl acetate extraction F
F OH
precipitation into pentane
OH
O
N
OH OCa 1/2
N
1. aqueous Ca(OAc)2
OH
O ONa
Atorvastatin amorphous 2. water extraction HN
O
Atorvastatin ethyl acetate solution
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HN
removal of NaOAc
30
O
in ethyl acetate
heptane solution of starting material and impurities
HISTORY OF THE ZENTIVA PROJECT
● Selected process failed ● Alternate process developed, but Kaneka had an exclusive contract ● Supplier of the penultimate intermediate was found ● Triethylammonium salt process developed – Et3N impurity ● Extractive process developed ● Stability problems (oxidations) ● Oxygen scavengers solved the problem (price) ● Pakaging under nitrogen used
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ZENTIVA ATV REGISTRATIONS (DONE, PENDING, PLANED)
Torvacard -
registered in 15 countries out of Europe
-
10 markets under registraiton
-
Production in Zentiva SK for ……. (small globe)
-
API production: Hlohovec
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3. Case Study II Sartans
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SARTANS CURRENTLY ON THE MARKET Cl
N
N N
Bu N
HO
N
N
NK
N
O
losartan potassium COZAAR Bu N
HOOC
N N NH N
OEt N
Me
O
O
O
O
candesartan cilexetil ATACAND
valsartan DIOVAN
N N
HO
Pr
O O
NH
N
O
SARTANY
N
irbesartan APROVEL
N N NH N
O
N N
Bu
N
O O
N N NH N
Pr
N N N
COOH
O olmesartan medoxomil BENICAR
telmisartan MICARDIS N
S HOOC
OEt
N
N
Bu N
O
O
O O N
N
K
O COOH eprosartan TEVETEN
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O O azilsartan (ka)medoxomil EDARBI
34
LOSARTAN – MERCK PROCESS
N N N N
Br
Cl
Tr
Cl +
N Bu
O
A
N Bu
O
N
N N
N N - + N K N
Cl C,D
A: K2CO3, DMA, 0-5°C B: NaBH4, DMA C: H2SO4, i-PrOH, heating D: KOH, cyclohexane, MEK, distillation and crystallization Challenges in generic API development
N Bu
HO
N
TrLos
losartan K
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N
Tr
B
Bu HO
N
N H
BBTT (TTBB) Cl
N N
35
N N Tr N N
DIMERIC IMPURITIES OF LOSARTAN – MERCK PROCESS Cl
N Bu N
HO
N N
N NH
losartan Chemical Formula: C22H 23ClN6O Exact Mass: 422,16 Cl Cl Cl
N Bu
HO
N
N N
N Bu
N N
N
N N
N Bu
N N
NH Cl
N Bu
HO
N
N N NH N
N N N N
Imp. II
Imp. I
Chemical Formula: C44H44Cl 2N12O Exact Mass: 826,31
Chemical Formula: C44H 44Cl 2N 12O Exact Mass: 826,31
Losartan produced by acid detritylation contains 2 dimeric impurities in a ration 1 : 1 April 7th, 2014
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LOSARTAN – ZENTIVA PROCESS
Cl
N Bu
HO
N
Cl
N N Tr N N
N Bu
A
N
HO
N N - + N K N
+ TrOMe
> 80 %
losartan K
TrLos
A: KHCO3, MeOH, reflux 10 h Material cost [ €/kg ]
Labour cost [ €/kg ]
Quality overheads [ €/kg ]
Production overheads [ €/kg ]
Logistic overheads [ €/kg ]
COGS [ €/kg ]
Losartan K
129.18
12.16
11.75
125.81
10.09
288.99
Losartan K NT
105.25
10.05
4.25
104.03
8.22
231.80
Technology
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CANDESARTAN CILEXETIL AND OLMESARTAN MEDOXOMIL ZENTIVA PROCESS
H 3C
H 3C N O O O
N
CH 3 O
N N N Tr N
N A
O O
70 % O
O
O
N
CH 3 O
N N N H N
O
O
candesartan cilexetil
H 3 C OH
H3 C OH H 3C
O O
O
O
N N
O
Me
H 3C
O N N N N Tr
A 68 %
O
O
O
N N
O
Me N N N N H
Me
Me
olmesartan medoxomil
A: aq. MeCN or acetone, reflux
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AZILSARTAN MEDOXOMIL - PROCEDURE PUBLISHED BY TAKEDA N
N OEt
OEt NH 2OH . HCl MeONa or Et 3N
N MeO
CN
O
N
N MeO
Refs 1-3
N
O
NH 2
IIa
OEt
ClCOOR Et 3N or Py Refs 1-3
55 %
Ia
OH
N MeO
O N
O
OEt O N
N O
O NH
O
O
Cl
Ref . 4
O O O azilsartan medoxomil
N OEt
medoxomil chloride Et 3N, DMF
N HO
OEt
O O N
NH
O
14, 22 % chromatography
LiOH or NaOH aq. MeOH Refs 1-3
MeO
IVa
Total yields 1,4 - 5,9 % Challenges in generic API development
O
80-94 % azilsartan
39
O O N
N
1. US 5,583,141; EP 0,520,423. 2. Kohara Y., Imamiya E., Kubo K., Wada T., Inada Y., Naka T.: Bioorg. Med. Chem. Lett. 1995, 5, 1903-1908. 3. Kohara Y., Kubo K., Imamiya E., Wada T., Inada Y., Naka T.: J. Med. Chem. 1996, 39, 5228-5235. 4. US 2009/0270464, EP 1718641; EP 2119715.
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O NH2
xylene, reflux Refs 1-3
N
O
R
IIIa
23, 52 % chromatography
O N
O
NH
PROCEDURE PUBLISHED BY TAKEDA – 1ST STEP
OEt
OEt
CN
O
MeO
O
OH
N
N MeO
H N
N
N
N
O
N
NH 2
O
O A
IIa
Ia
Reproduction of the published procedures: Method A: MeONa/MeOH, DMSO, 90 °C, 4 h Method B: Et3N, DMSO,90 °C, 15 h
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N
ZENTIVA PROCEDURE – 1ST STEP
OEt
OEt
CN
O
MeO
O
OH
N
N MeO
H N
N
N
N
O
N
NH 2
O
O A
IIa
Ia
Zentiva approach - use of aqueous hydroxylamine: Selected conditions: aqueous 50 % w/w hydroxylamine, DMSO, 90 °C, 15h Typical HPLC of the crude product:
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N
PROCEDURE PUBLISHED BY TAKEDA – 2ND AND 3RD STEP N
N
OEt N MeO
OH N
O
NH2
R
N MeO
O N
OEt O NH2
O
IIa
IIIa
Challenges in generic API development
MeO
O
IVa
42
O O N
N xylene, reflux Refs 1-3
Reproduction of the published procedures: Method A: R = Et; 1st step – THF, Et3N, 2nd step – xylene, reflux 1.5 h Method B: R = 2-ethylhexyl; 1st step – DMF, Py, 2nd step – xylene, reflux 2 h
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N
OEt
ClCOOR Et 3N or Py Refs 1-3
O
NH
ZENTIVA PROCEDURE – 1ST STEP
N
N OEt N RO
OH N
O
II
NH2
reagent solvent base
OEt N RO
R = Me, Et
O N
O
IV
Use of diethylcarbonate: Selected conditions: DEC, EtONa, RT Typical HPLC of the crude product:
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O
43
NH
ZENTIVA PROCEDURE
OEt
CN
O
OEt
50 m% aq. NH2 OH DMSO, 90 °C
N EtO
N
N
N
N EtO
85 %
OH N
NH 2
O
aq. NaOH 95 %
O
O O- K+
N
O N
N N- K+
acetone, RT O
O
O
OEt
O
OEt
O N
NH
O O azilsartan kamedoxomil
O
HO
85 %
O O azilsartan medoxomil
Challenges in generic API development
HO
O
azilsartan
44
O
OEt N
TsCl,
Rádl S.: CZ 304252; WO 20120139536 Rádl S., Stach J.: CZ 303505; WO 20120139535 Rádl S., Černý J., Stach J., Holec J., Píša O., Gablíková Z.: J. Heterocycl. Chem. 50, 929 (2013). Rádl S., Černý J., Stach J., Gablíková Z.: Org. Proc. Res. Dev. 17, 77 (2013).
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N
O
O O
O
NH
O
IVb
O
N
EtO
IIb
N
O N
N
80 %
Ib
O
OEt
DEC EtONa RT
O N
NH
4. Conclusions
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RULE OF THUMB FOR GENERIC API DEVELOPMENT
● Development of API must start ASAP ● Backward engineering – analysis of original drug product just after the launch
● Solid form screening and selection (salts, polymorphs, cocrystals) ● Three principally different approaches to the API Synthesis o Improvement of the basic patent procedure o Different chemistry with the common intermediates with the basic patent approach
o Quite different innovative approach
● Usually the „common intermediates“ approach is the most successfull from the long-term perspective
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ORIGINAL VS GENERIC DRUG BUSSINESS
● Innovator firms have been supplying generic products for years ● FDA estimates that innovative pharma companies manufacture over 50% of generic products
● Most inovative pharma companies are involved in generic business in many ways
o Owning stock of generic companies o Having own generic branch (Pfizer – Greenstone; Novartis – Sandoz; Daiichi Sankyo – Ranbaxy; Sanofi - Zentiva)
o Licencing generics from generic companies (Pfizer – Aurobindo)
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DĚKUJI ZA POZORNOST
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DĚKUJI ZA POZORNOST
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50
Encyklopedický farmaceutický slovník VŠCHT Praha, 2014 Editor: M. Kuchař Autoři okruhu Chemické procesy, chemická léčiva: S. Rádl, F. Hampl 481 hesel, 140 obrázků, 66 odkazů
VŠCHT Praha, 2007 http://vydavatelstvi.vscht.cz/knihy/ ISBN 978-80-7080-639-5 April 7th, 2014
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VŠCHT Praha, 2014 http://vydavatelstvi.vscht.cz/knihy/ ISBN dosud nepřiděleno 51
