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…

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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…

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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

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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)

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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