hamari chemicals ltd. “technology for life” 1. who are we? global supplier of custom...
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Hamari Chemicals Ltd.
“Technology for life”
1
Who are we?
Global supplier of custom manufactured API’s and Intermediates
Established in 1948 Turnover: 5.6B Yen (USD ~70M) [2011]
22
Locations
3
Custom Chemical Manufacturing Technology
More than 60 different synthesis reactions on commercial scales
Strengths: Amino acid derivatives Oligopeptides
Optically active compounds
4
1948 Hamari’s first product: Saccharin
1950 First API: Quinine Ethylcarbonate
1957 First custom synthesis: Orotic acid
1961 First Amino acid: DL-Methionine
1962 First Amino acid derivative: Methyl Methionine Sulfonium Chloride
1966 First peptide in laboratory: L-Leucil L-Leucine
1968 First peptide on commercial scale: L-Glycil, L-Glycine
1970 First peptide on a multi-ton scale: β-Alanyl L-Histidine
5
A look back to the beginning……
1970 First contract manufacturing: protected Amino Acids
1976 First contract manufacturing with multi-step synthesis
1985 First FDA approved product: Ibuprofen
1997 FDA inspection of the Yonezawa facility
2001 ISO 14001 Certification of the Yonezawa facility
2002 launch Zinc Carnosine in US marketplace
2006 Two Separate FDA inspections of the Yonezawa facility
2008 Establishment of a high-potency laboratory and a kilo-scale laboratory in the
Osaka facility
2008 Establishment of the Kobe laboratory
6
A look back to the beginning…… cont.
Sales in 2011
Intermediates: 31.9% API: 52.5%
Nutritional Ingredients: 8.5% Others: 7.1%
Intermediates API Nutritional Ingredients Others
Sales volume: 71 million USD (Fiscal 2011)
31.9 %
52.5 %
7.1 %8.5 %
7
Our customers by region
Europe: 7.1 % America: 4.2 %
Japan: 86.1% Others: 2.6 %
America Europe Others Japan
7.1 %
2.6 %
4.2%
86.1 %
8
Product Name Manufacturing Site
Annual Production
AmountDelivery Location
Polaprezinc /Zinc Carnosine
Yonezawa 11 t Domestic and USA
Benfotiamine Yonezawa 50 t Domestic and Europe
Tamsulosin HCl Osaka 26 kg Domestic
API Examples (Commercial Products)
* Final intermediate
9
Chemical Name Brand name Trademark
Zinc Carnosine Pepzin GI(L-Carnosine Zinc complex)
Benfotiamine BenfoPure(Vitamin B1 derivative)
L- Carnosine CarnoLife(β-alanyl-L-histidine)
Food Supplement Products Sold in the USHamari has been supplying food supplement ingredients to the US market
for over than 20 years.
10
Hamari is a commercial product company with global sales
11
Hamari is a full chemical development service company
Hamari Chemical USA San Diego Research Center
“Technology for life”
12
Competitive advantage of a process R&D lab in San Diego
Position ourselves as an extended process R&D lab for the local pharmaceutical and biopharmaceutical companies on need basis
Easy access to clients and open lab policy to our clients (time zone and location)
Easy access to reagents and fast turn-around time
Easy access to instruments
Easy on cost: $20,000/month/FTE
Easy access to supporting structure in Japan
State of art facility (Neurocrine’s process R&D lab) and supporting structure
Systematic process R&D approach
13
History, equipment and capability
Established in 2011 in the Neurocrine Building in Carmel Valley, North San Diego
7 hoods and 2 walk-in hoods
50 L, 20 L, and 10 L Chemglass jacketed reactors
In house Agilent 1100/MSD LCMS, Agilent 1200 HPLC and 300 MHz NMR
Access to DSC, TGA, FTIR, XRD at UCSD
Specialized in chiral technology, peptide chemistry, building blocks and heterocyclic molecules
Systematic process R&D from the 1st kg synthesis to commercial process
Synthesis of chiral molecules via chiral resolution, chiral pool, asymmetric synthesis, catalytic asymmetric synthesis
14
Turn a discovery route into a robust manufacturing process
Replacement of column chromatography with precipitation/crystallization
Avoid using expensive and non-environmentally friendly solvents/reagents
Establish robust IPC for reaction
Seeking volumetric efficiency and increase throughput
Replacing drying reagents with azeotropic drying
Determining ratio of solvents for any solvent swaps and completion of drying
Avoid concentration to dryness
Streamline the work up process by eliminating unnecessary steps
15
Route scouting/selection for new scalable processes
Critical evaluation of a process and process parameters for scalability and potential for manufacture on large scale
Conducting thorough literature search for a target molecule or a process
Generating new innovative solutions to complex synthetic problems
Design synthesis for least number of regulatory steps
Seek for crystalline intermediates for purification
Design synthesis to avoid GTI intermediates
Rapid turnaround for testing ideas
Speedy communication
16
Systematic optimization of chemical processes
Systematic screening of reaction parameters such as solvents, temperature, stoichiometry of reagents, concentration, order of addition, reaction time, rate of agitation etc.
Establish acceptance criteria for key starting materials and intermediates
Stress testing for stability of intermediate and product during reaction, work up, isolation, under drying condition and for storage, shipping and handling
Identify appropriate ranges for key process parameters by performing DOE
Identify critical parameters which will impact the quality of product
Preparation of development report and draft manufacture documents
Technology transfer to manufacturing production
Safety evaluation/hazard assessment
17
Yonezawa HamariHamari (Osaka)
Manufacturing Department
Plant Manager
QCSection
QASection
Technology Department
QADept
Group1
Group2
Group3
International Dept.
Board Member
QCSection
Group1
Group2
Group3
Domestic Sales& Marketing Dept
QADept.
ManufacturingDept.
Sales Section 2
Sales Section 1
President
PurchasingDept.
Kobe Lab
R&DDept
USAGermany
Shanghai Project Management Office
18
Hamari Chemicals organization chart
HamariSDRC
Hamari Chemicals-OsakaHamari Chemicals-Osaka
R&D Dept. (36)Manufacturing Dept.(14) Process Development Scale up, Pilot production non-GMP Production GMP Production
Sales &Marketing Dept.(12)International Dept.(4)
QA Dept.(5)QC Section (9)Analytical studyMethod ValidationStability Test
Manufacturing gram-100 kg(Lab, Pilot, Pre-clinical , PhⅠ , Ph a)Ⅱ
Manufacturing gram-100 kg(Lab, Pilot, Pre-clinical , PhⅠ , Ph a)Ⅱ
Yonezawa Hamari ChemicalsYonezawa Hamari Chemicals
Technology Dept.(10) Process Optimization GMP Production Process Validation
Manufacturing 50-200kg(Ph b, Ph , Validation, Commercial)Ⅱ Ⅲ
Manufacturing 50-200kg(Ph b, Ph , Validation, Commercial)Ⅱ Ⅲ
TechnicalTransfer
TechnicalTransfer
QA Dept.(9) CMC Preparation Pre-approval InspectionQC Section (21) Method Validation Stability Test
Manufacturing Dept.(87) GMP Production Validation Batch Commercial Production
19
Quality and R&D Employees
Research & Development Total Osaka Yonezawa
New products 3 3 0
Process Chemistry 43 33 10
Quality Total Osaka Yonezawa
QA 14 5 9
QC 30 9 21
20
Hamari Osaka
Size 1970 m2
New low temperature cooling system
Total reactor capacity > 21 m3 , from 50 – 2000 L
0.5 KPa – 0.96 MPa , -90 – 150˚C Two clean rooms Autoclaves, resin columns,
centrifuges, dryers, mills…
21
Hamari Yonezawa
Size 52.806 m2
Production started in 1981 Total reactor capacity >240 m3,
from 200 – 5000 L 12 independent product lines Kilo laboratory 1.3 Kpa – 6.8 MPa, -50 – 150˚C Autoclaves, centrifuges, dryers,
mills, resin columns…
22
Yonezawa API plant
Glass-lined 5
Stainless Steel 12
Vertical Dryer 2
Autoclave (1 Mpa) 2500 L
2323
Ala-His-Lys
More than 30 years of experience in peptide synthesis.More than 30 years of experience in peptide synthesis.
H2NN
CO2H
NH Tfa
O
HN
N CO2H
HN NH 2
O
Tfa-Lys-ProL-Carnosine
H2 n
N
ZnO
N
N
O
O
N
H
: 5 tons
Capacity / kg to ton scale
Zinc Carnosine / Polaprezinc - API in Japan
- Dietary supplement in USA
Peptide Manufacturing
N
NH
HN
H2N
Me HN NH 2
CO2H
O
O
24
Capacity (maximum per year)di-peptide: 50 tonstri-peptide: 20 tonstetra-peptide : 10 tonspenta-peptide: 10 tonshexa-peptide: 5 tons
Peptide Manufacturing
Expertise in small to medium length molecular peptides.
Extensive technology using Solution Phase Synthesis.
Experience in cGMP synthesis for clinical studies.
NEW-Acquired resources and equipment for Solid Phase Synthesis.
Peptide projects di-peptide : 9 tri-peptide: 10 tetra-peptide: 7 penta-peptide: 6 hexa-peptide: 1 hepta-peptide: 1Nona-peptide: 1 deca-peptide: 1 Peptide mimic: 1Total projects (2006-2011) 37
Manufacturing Experience
Intermediates forIntermediates for
- ACE inhibitors - ACE inhibitors
- Anti-cancer drugs- Anti-cancer drugs
- - HIV protease inhibitorsHIV protease inhibitorsCosmetic substancesCosmetic substancesDietary supplementsDietary supplements
Custom Manufacturing
25
ACE InhibitorsACE Inhibitors
Lisinopril Ester/FARGA-3 (Europe)
Di-peptide Derivative (Japan)
Di-peptide Derivative (Japan)
Peptides - Custom Manufacturing
NH
O
N
CO2H
N CF3
O
H
O OC2H5
Commercial (Yonezawa) Capacity : 30 tons / year 30 tons / yearPurity : >99% , RSS: <0.5%In accordance with cGMP In accordance with cGMP
Manufacturing
Commercial (Yonezawa) Capacity : 1.5 tons / year 1.5 tons / yearIn accordance with cGMP In accordance with cGMP
Manufacturing
Commercial (Yonezawa) Capacity : 500kg / year 500kg / yearIn accordance with cGMP In accordance with cGMP
Manufacturing
26
Anti-Cancer DrugsAnti-Cancer Drugs
Peptides - Custom Manufacturing
Commercial : Currently ongoing
Hexa-peptide 150 kg / year (25 kg / Lot) His, Trp, Ser, etc…Tri-peptide 30 kg / year (15 kg / Lot) Arg, etc…
IND Products : 2006-2011
Tri-peptideTri-peptide 11 ProjectsProjects 30 kg 30 kg (2008)(2008)Tetra-peptideTetra-peptide 2 Projects2 Projects 1kg, 1kg 1kg, 1kg (2010) (2010) Penta-peptidePenta-peptide 4 Projects 4 Projects 10 kg, 15 kg, 10 kg10 kg, 15 kg, 10 kg (2008)(2008)Deca-peptideDeca-peptide 1 Project 1 Project 50 g 50 g (2008) (2008) Hepta-peptideHepta-peptide 1 Project 1 Project 1 kg1 kg (2009)(2009)Peptide mimic Peptide mimic 2 Projects 2 Projects 10 kg 10 kg (2006) (2006)
2 kg, 8 kg 2 kg, 8 kg (2007) (2007)
27
Peptides - Custom Manufacturing
Intermediates and API for LH-RH analoguesIntermediates and API for LH-RH analogues
APO(Ac-D-2-Nal-D-4-ClPhe-D-3-Pal)Registry Number:129225-22-5
HPLC purity : NLT 99%
Peptide-L-Arg(nitro)-Pro-D-Ala-NH2 Peptide-Lys(Ipropyl.X)-Pro-D-Ala-NH2
We are able to provide our process development for intermediates and API of LH-RH analogs such as Degarelix and Abarelix etc…
NH
Cl
O
HN
O
OH
N
OHN
O NH
O
N
O NH
O
NH2
NH
N NHO2N
peptide NH
O
N
O NH
O
NH2
NX
X:Cbz-, BOC-, Fmoc-
peptide
28
API and Intermediates for antiviral agents API and Intermediates for antiviral agents
Nucleic Acid Derivatives
IND Products IND Products :: 2007-20102007-2010Anti HIV project ; non-GMP 2 Lot (1 kg, 15 kg); GMP 1 Lot (3 kg)Anti HIV project ; non-GMP 2 Lot (1 kg, 15 kg); GMP 1 Lot (3 kg)
O
NHO
HN
O
OMe
HO OHHO
O
NHO
HN
O
OMe
HOHO
O
NHO
HN
O
OMe
R
O
NHO
HN
O
OMe
HO OHR
O
NHO
HN
O
OMe
HOR
O
NPvO
HN
O
OMe
HO OHOHC
O
NRO
HN
O
OMe
O OOHC
29
Reduction Reactions
Osaka
500L Hastelloy 1.0 MPa500L SUS 0.5 MPa100L SUS 0.2 Mpa10L SUS 2.0 Mpa1000L GL 0.1 Mpa
Autoclaves
Catalysts & Reagents
Pd-C
SBHRed-AlLAH
Rh-Alumina
Pt-CRaneyNi
DIBAH
Extensive experience in safely handling Metal catalysts.
Yonezawa
2500L SUS 1.0 MPa1800L SUS 1.0 MPa1700L SUS 1.0 MPa1000L SUS 0.2 MPa500L SUS 6.8 MPa
Our capability to use chemical reagents
30
R1
CO2R2
O
NH2N
O
NH
CF 3
O
CO 2H
DIBAH
Raney Ni+
-50 to -60 ℃
H2
NNH
R1
O
NH
CF 3
O
CO 2H
CO 2R2
Reduction with DIBAH on commercial scale
Asymmetric Schiff base reduction (H2 / Raney Ni , 30 tons / year)
Horner-Emmons reaction(EtO)2POCH2CO2Me
Reductive aminationNaBH(OAc)3N
R CO2MeN
R CHO
Reduction Experience
Pd-CH
CO2EtEtO 2C
ClH2
H
CO2EtEtO 2C
Cl
Selective hydrogenation by using Pd-C ( without dehalogenation )
N
R
CO2Me
N
R
HN R
31
Please note ! - Asymmetric synthesis Instead of optical resolution. - When it is not appropriate to use other catalysts.Hamari is able to provideFull Time Equivalent study needed for your custom synthesisUsing our Asymmetric Transfer Hydrogenation technology.
Please note ! - Asymmetric synthesis Instead of optical resolution. - When it is not appropriate to use other catalysts.Hamari is able to provideFull Time Equivalent study needed for your custom synthesisUsing our Asymmetric Transfer Hydrogenation technology.
Asymmetric Transfer Hydrogenation using Chiral Ru- and Ir -catalysts
O
Me
R
[H]
Hamari catalyst(Chiral Ru-, Ir-catalyst)
N
Me
R
H2N
Me
RHN
*
NX
N
Cl
ArHet
O
H
H
Rn
40-80%ee
R
O
N Me Hamari catalyst(Chiral Ir-catalyst)
R
O
HN Me
[H]
X=Ru , Ir
Hamari Chiral Technology
70-90%ee
Chiral Ru-complex ee(%) .arene-Ru( )-TsDPENⅡ ca.20%eeHamari catalyst Ru 40%ee
Hamari catalyst Ir 80%ee
Chiral Ru-complex ee(%) .arene-Ru( )-TsDPENⅡ ca.20%eeHamari catalyst Ru 40%ee
Hamari catalyst Ir 80%ee
32
Olefination -Horner-Emmons and Wittig reactions
Horner-Emmons
Alkylation
EtherificationPTC-catalyzed (e.g. TBAB)Mild condition (<80℃)High yield (>90%)
~ - 90 max. 1000L℃ ~ - 50 max. 3000L℃
n-BuLi, LDA, NaH, tert-BuOK, tert-BuONa, MeONa, Li, etc.
Base
NH
OR
Quinoline & Quinazoline DerivativesCarbazole Derivatives
Grignard ReactionO
Cl R Cl
OH
R CO2H
OHR-MgBr
CuI
CN
H
O
Ph3PCH2R2Br+ -
tert-BuOKNaOMe
(EtO)2POCH2CN
R2
Cryogenic reactionsCryogenic reactions
Y
X
OAr
R1
R2
Mitsunobu reaction using DIAD
R
OH
R
ORR-OH
DIAD*, PPh3
* DIAD : Diisopropyl azodicarboxylate
Wittig
33
ZnBrR1 Br R2
R1 R2
+
Pd(dba)2
PPh3
I
R1
R1
R2(HO)2B
R2
Pd(OAc)2
ligand, base+
Pilot plant : Osaka Manufacturing : 50kg / BatchResidual Residual Pd : NMT 1 ppm levelIn accordance with In accordance with cGMP
Manufacturing
Commercial : YonezawaManufacturing : 100kg / BatchResidual Pd : NMT 1 ppm levelIn accordance with In accordance with cGMP
Negishi , Suzuki and Heck
R1
X
+ R2
Pd(OAc)2
ligand, base
R1
R2
Manufacturing
Commercial : YonezawaManufacturing : 100kg / BatchResidual Pd : NMT 1 ppm levelIn accordance with In accordance with cGMP
Manufacturing
Negishi Cross Coupling
Suzuki-Miyaura Cross Coupling
Mizoroki-Heck Reaction
34
R
N
R
N
NR
N
Quinolines Isoquinolines Quinazolines
Aminothiazoles
NH
OR
Carbazoles
NH
R
CO2H
NO2
Indoles
Heterocyclic Derivatives
S
NCO2R2
H2N
N OR1
S
R1 R2
R3
Thiophenes
N
N
CH 3
NH
R
O
Imidazoles
O
N
Me
OH
Oxazoles
35
Nitration Reduction
Oxazole DerivativesLiAlH4
L-Asp(OMe)-OH
Heterocyclic Derivatives
H2N
O
OH
OMe
O
Leimgruber - Batcho indole synthesis
Oxazole synthesis and the following LiAlH4 - reduction
O
N
OMe
OMe
O
N
Me
OH
R
Me
R
Me
NO2
R
NO2
N
R
NH 2
N
NH
R
Indole Derivatives
ROMe
O
NitrationR
OMe
O
NO2
Reduction
ROMe
O
NH 2
Quinazolins synthesis
Quinazolines
NH
N
O
R
36
Oxidation
CAN : (NH4)2Ce(NO3)6
CAN,NaBrMe CH 2Br
TEMPO
OHR
HR
O
TEMPO (1mol%)
NaBr, NaClO aq.
Oxone®; Potassium Peroxymonosulfate
S
O
S
Oxone®
Safely handling reagents such as CAN, TEMPO,Oxone® MnO2 and Sulfonium salts (Swern oxid.)
N
CH 3
CH 3
CH 3
CH 3
O
OHR HR
OMnO2
MnO2 : activated type
Swern and related oxidations
DMSO / WSC
ROH
MeMe
RH
O
MeMe
R1
R2
Me
OH
R1
R2
Me
O
(COCl)2 / DMSO -60℃
37
High temperature reactions (200-300 )℃
Precise Distillations for Purification
Phosgene Chemistry
Reductions using Diborane
Oxidations using Ozone
Photo-reactive Chemistry
Types of reactions that Hamari is unable to perform
38
Back up slides
“Technology for life”
39
ReactorOsaka plant 2000 1500 1200 1000 500 200 100 50 10 Total
Total (m3)
Reactor
GL 1 3 5 3 2 1 1 16 12.65
SUS 1 1 4 2 2 1 11 9.00
Autoclave
GL0.1
Mpa1
SUS0.48Mpa
0.19Mpa
0.48Mpa
3
Hastelloy0.96Mpa
1
Yonezawa plant
5000 4500 4000 3000 2500 2000 1800 1700 1600 1500 1200 1000 800 500 200Tota
l
Total
(m3)
Reactor
GL 2 - 5 14 1 19 - 3 - 11 4 2 2 5 3 72 145.6
SUS - 1 - 6 5 20 3 1 1 12 - 14 5 6 1 75 122.9
Autoclave SUS0.96 Mpa
0.96 Mpa
0.96Mpa
0.19Mpa
0.68Mpa
5
Clean room ・ 2 systems GL 1000L GL 200L
Clean room ・ 2 systems ・ GL 2000L , GL 800L, GL
200L ・ GL 3000L , SUS3000L
Clean room ・ 5 systems ・ GL 3000L×2 , GL 2000L, GL
1700L, ・ SUS3000L
40
Equipment list
Osaka Centrifuge Filter Dryer Mill
24inch
36inch
Vacuum Press DBL Con Tray DryerVacuum Tray
DryerCutter
MillPin Mill
Rubber-lined 1 2
SUS 2 4 4 3 1(200L) 3 1 2 1
GL 1 1 1(800L)
Teflon-lined 1 1
Yonezawa Centrifuge Filter Dryer Mill
36inch
42inch
48inch
Vacuum PressDBL Con
Vertical Dryer
Tray Dryer
Vacuum Tray Dryer
Cutter Pin Ball Hammer
Rubber-lined
4 1
SUS 19 3 1 8 19 3 8 5 5 6 3 1 3
GL 1 2 4
Teflon-lined 2
Spray Dryer, Column, Centrifugal-flow Thin-film Vacuum Evaporator, purified water system, etc.
41
Other Equipments
Equipment ModelOsaka Yonezawa
QC R&D QC R&D
HPLC Gradient PDAUV
34
129
113 6
UPLC or UFLC PDAUV
12
1
HPLC Iso UVIon Chromatography RI
111
4
1
8
1
4
GC Capillary FIDHead space sampler
31
1 72
GC Packed
FID/TCDFID/ECD
1 11
LC/MS 1
GC/MS 1
NMR Varian 200MHz 2
42
Analytical instrument list
Equipment Maker Osaka Yonezawa
Atomic AbsorptionSpectrophotometer
Shimadzu 1
Laser Diffraction Particle Size Analyze Malvern 1
TOC Hiranuma 1
FT/IR Shimadzu, Jasco 1 2
UV Spectrophotometer Shimadzu, Jasco 1 1
Polarimeter Jasco, Horiba 1 1
Karl Fischer Kyoto Electronics, Mitsubishi 2 2
Electrometric Titrator Kyoto Electronics, Hiranuma 1 2
DSC Rigaku 1
TG-DTA Rigaku 1
XRD Rigaku 1
Toxinometer Charles River, Wako 1 1
43
Analytical instrument list – cont.
14
90
14
Authorities
Domestic clients
Foreign clients
Number of Audits
Audit Experience (2008-2010)
Osaka Yonezawa
2 12
27 63
3 11
44
42
6
17
4
Domestic
Abroad
Number of trialsIntermediate API
Clinical Trials Supported
45
(IND manufacturing in 2008-2010)
Type Ⅱ 2
EDMF 1
Korea 2
Client’s DMF 2
DMF’s Held by Hamari
DMF Number Status Type Submit Date Holder Subject
21259 A Ⅱ 1/14/2008 YONEZAWA HAMARICHEMICALS CO LTD
POLAPREZINC ASMANUFACTURED IN YAMAGATA, JAPAN
DMF Number Status Type Submit Date Holder Subject
23196 A Ⅱ 10/18/2009 YONEZAWA HAMARICHEMICALS CO LTD
LULICONAZOLE ASMANUFACTURED IN YAMAGATA, JAPAN
46
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