Technology for Life 1 Who we are Global supplier of custom - PowerPoint PPT Presentation

“Technology for Life” 1

Who we are  Global supplier of custom manufactured API’s and Intermediates  Established in December 10, 1948  Turnover: USD ~80M [2014] 2

Locations Europe Office China Office Frankfurt, Germany Shanghai San Diego Research Center Hamari Chemicals USA Inc. Commercial Plant Chitose Hamari Chemicals, Ltd. Commercial Plant Yonezawa Hamari Chemicals, Ltd. Kobe Research Center Tokyo Office Hamari Chemicals, Ltd. Kobe Technolab Head Office, R&D, Pilot Plant Hamari Chemicals, Ltd. Osaka 3

Custom Chemical Manufacturing Technology More than 60 different synthesis reactions at commercial scale Strengths: Unnatural Amino acids Long chain peptides Optically active compounds 4

A look back to the beginning…  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 -Leucyl L -Leucine  1968 first peptide on commercial scale: L -Glycyl L -Glycine  1970 first peptide on a multi-ton scale: β -Alanyl L -Histidine  1970 first contract manufacturing: protected Amino Acids 5

 1976 first contract manufacturing with multi-step synthesis  1985 first FDA approved product: Ibuprofen  1997 FDA inspection of the Yonezawa facility (Yonezawa Hamari Chemicals, Ltd.)  2001 ISO 14001 Certification of the Yonezawa facility  2002 launch of Zinc Carnosine on the US market  2006 two separate FDA inspections at the Yonezawa facility  2008 establishment of a high-potency laboratory and a kilo-scale laboratory at the Osaka facility (Hamari Chemicals, Ltd.)  2008 founding of the Hamari Chemicals, Ltd. Kobe Technolab  2011 founding of Hamari Chemicals USA Inc. San Diego Research Center  2013 FDA inspection at the Yonezawa facility  2013 acquisition of Chitose Hamari Chemicals, Ltd. 6

Sales in 2014  Sales volume: 80 million USD (Fiscal 2014) Cosmeceutical & Nutraceutical Others (6%) Ingredients ( ７ %) Active Pharmaceutical Intermediates (30%) Ingredients (57%) 7

Our customers by region USA(4% ) EU(1%) Others (2%) Japan (93%) 8

API Examples (Commercial Products) Annual Manufacturing Product Name Production Delivery Location Site Amount Polaprezinc / Yonezawa 11 t Japan and USA Zinc Carnosine Benfotiamine Yonezawa 50 t Worldwide Tamsulosin HCl Osaka 26 kg Japan * Final intermediate * Final intermediate 9

Food Supplement Products Sold in the US Hamari has been supplying food supplement ingredients to the US market for over than 20 years. Chemical Name Brand name Trademark  Zinc Carnosine PepzinGI ( L -Carnosine Zinc complex)  Benfotiamine BenfoPure (Vitamin B1 derivative)  L - Carnosine CarnoLife ( β -alanyl- L -histidine) 10

Nutraceuticals/Cosmeceuticals OTC Products/Natural Extracts Generic Pharmaceuticals Novel Pharmaceuticals University • Technology Licensing Organization Bio-Venture 11

The organizational chart of Hamari Group Hamari (Osaka) Yonezawa Plant Chitose Plant President Board Members Purchasing International QAU Plant Manager Plant Manager Dept. Dept. Manufacturing R & D Sales &Marketing Dept. Dept. Dept. EHS Office QA Dept. Project Management QA Dept. Office Section 1 QA QA Section Group 1 QA Section Manufacturing Section Dept. Technology QC Group 2 QC Dept. Section QC Section Section 2 Section Manufacturing Group 3 Shanghai Environment Control Dept. office Dept. Hamari No.1 Group 4 USA Section Production Management Dept. No. 2 Kobe Lab. Europe Section Engineering & office Maintenance Section Material Management No. 3 Section Section Packaging & Labeling Engineering & Section Maintenance Section 12

Yonezawa Hamari Hamari -Osaka Technology Dept. (14) Domestic Sales & QA Dept. (13) Marketing Dept. (11) QC Section (25) International Dept. (6) Manufacturing Dept. (74) R&D Dept. (37) Project Management (2) Manufacturing Dept. (1 ３ ) QA Dept. (6) Manufacturing 50 to 200kg Scale-Up QC Section (9) (Ph Ⅱ b, Ph Ⅲ , Validation, Commercial) Transfer Project Management (7) Manufacturing gram to 100 kg Chitose Hamari (Lab, Pilot, Pre-clinical ， Ph Ⅰ ， Ph Ⅱ a) QA Dept. (2) Synthesis QC Section (5) Transfer Manufacturing Dept. (8) Manufacturing 50 to 100kg Hamari USA Inc. (Ph Ⅱ b, Ph Ⅲ , Validation, Commercial) San Diego Research Center 13

Quality and R&D Employees Research & Total Osaka Yonezawa Chitose Development New products 3 6 0 0 Process 39 37 13 0 Chemistry Quality Total Osaka Yonezawa Chitose QA 15 6 13 2 QC 29 9 25 5 14

Osaka  Size: 1970 m 2  Work Shift: Daytime (adjustable)  Waste Water: incineration, public sewage treatment  Water: potable, deionized  Low Temperature cooling system  Total Reactor Capacity: > 21 m 3  Reactors: 50L to 2000L, 17 GL, 10 SUS  Low Temp.: - 20˚C  High Temp.: 150 ˚C  Autoclaves: 3 reactors at 0.96 MPa (SUS 100L, 500L, Hastelloy 500L)  Controlled Areas: 2 lines (200L, 1000L) 15

Yonezawa  Size: 52,806 m 2  Initial Production Date:1981  Work Shift: Daytime (some evening shifts)  Waste Water: incineration, self-process  Water: potable, purified, deionized  Total Reactor Capacity: >270 m 3 Reactors: 50L to 5000L {72x GL(148m 3 ); 75x SUS(123m 3 )}   Low Temp.: - 90˚C  High Temp.: 150 ˚C  Autoclaves: 1 reactor at 0.2 MPa (SUS 1000L); 4 reactors at 0.96 MPa (300L to 2500L); 1 reactor at 6.8 Mpa (SUS 500L)  Controlled Areas: 4 areas (200L, 800L, 1000L, 2000L, 3000L) 16

Yonezawa API Plant 3  Glass-lined 5  Stainless Steel 12  Vertical Dryer 2  Autoclave (1 MPa) SUS 2500 L 17

Chitose  Size: 8,000 m 2  Land Size: 56,760 m 2  Initial Production Dates: Pharmaceutical 1999, Nutraceutical 1990  Acquisition Date: 2013  Total Reactor Capacity: >20 m 3  Reactors: 14 x GL (15 m 3 ); 6 x SUS (4.6 m 3 ) 18

Hamari USA Inc. San Diego Research Center Synthetic Route Scouting  Size 307 m 2  Seven 8’ hoods  Two 12’ walk -in hoods  5 to 50 L jacketed reactors  Parr hydrogenator and autoclave  Onsite LC/MS, HPLC and NMR  CHIRALPACK 1A, 1B, 1C, 1D and 1E columns  Combi-Flash automatic chromatography  Access to FTIR, TGA, DSC, XRD… 19

Reaction Vessels and Autoclaves Total Controlled areas Osaka 2000 1500 1200 1000 500 200 100 75 50 Total (m 3 ) Reactor 1. GL1000L, SUS1000L 2. GL200L, SUS200L GL 1 3 5 3 2 2 1 17 12.75 SUS 1 2 2 2 2 1 10 8.5 Reactor Hastelloy 1 1 0.5 Teflon-lined 1 1 0.075 0.49 0.2 Controlled areas SUS 2 MPa MPa 1. SUS3000L, GL3000L Autoclave 0.98 2. GL2000L, GL800L, GL200L Hastelloy 1 MPa 3. GL3000L, 2xGL2000L Total Yonezawa 5000 4500 4000 3000 2500 2000 1800 1700 1600 1500 1200 1000 800 500 200 50 Total (m 3 ) GL 2 5 14 1 19 3 11 4 2 2 5 3 1 72 145.4 Reactor SUS 1 6 5 20 3 1 1 12 14 5 6 1 75 122.9 1.0 1.0 1.0 0.2 6.8 SUS 5 Autoclave MPa MPa MPa MPa MPa Chitose Total (m 3 ) 2000 1500 1000 800 750 500 300 250 30 Total GL 2 2 6 1 2 1 14 15.0 Reactor SUS 1 2 1 1 1 6 4.6 Controlled rooms 1. GL1000L 6.0 Autoclave Hastelloy 1 2. GL1000L MPa 20

Other Equipment Osaka Chitose Filter Centrifuge Dryer Milling and Packing room Filter Centrifuge Dryer 1 GL Nutsche 1 SUS (30 inch) 1 DBL Cone 2 Milling and Packing Room 1 SUS Nutsche 4 SUS (30 inch) 1 DBL Cone 4 SUS Nutsche 4 SUS (36 inch) 3 Tray Dryer 2 Cutter Mill 1 Teflon-lined 1 Hastelloy (36 inch) 1 Tray Dryer 1 GL Vacuum 4 Vacuum Tray Dryer 1 Pin Mill 1 Filter Dryer 4 SUS Vacuum 1 Electric Sieve 1 Teflon-lined 1 Hastelloy Yonezawa Filter Centrifuge Dryer Milling and Packing room 3 GL Nutsche 1 SUS (30 inch) 7 Double Cone Dryer 8 Milling and Packing Room 12 SUS Nutsche 22 SUS (36 inch) 5 Tray Dryer 5 Cutter Mill 1 GL Vacuum 1 SUS (40 inch) 6 Vacuum Tray Dryer 1 Pin Mill 8 SUS Vacuum 2 SUS (42 inch) 7 Vertical Dryer 2 Hammer Mill 6 Plate and Frame Presses 1 SUS (48 inch) 1 Spray Dryer 4 Electric Shifter Sieve 2 Rubber-lined (36 inch) 1 Supersonic Wave Sieve 2 Teflon-lined (36 inch) 21

Analytical Equipment (1) Osaka Yonezawa Chitose Equipment Type TOTAL QC R&D QC R&D QC PDA or UV 7 34 19 10 2 87 HPLC UHPLC 1 4 7 1 1 Ion Chromatography 1 FID 5 1 6 1 TCD 1 2 1 24 GC ECD 0 Head Space Sampler 2 4 25 ˚C / 60%RH Yes Yes Yes YES Test Chambers 40 ˚C / 75%RH Yes Yes Yes 22

Analytical Equipment (2) Equipment Osaka Yonezawa Kobe Chitose TOTAL Atomic Absorption Spectrophotometer 1 1 LC/MS 1 1 Laser Diffraction Particle Size Analyzer 1 1 Potentiometric Titrator 1 2 1 4 FT/IR 1 2 1 4 Karl Fischer Titrator 1 3 2 6 NMR 200 MHz 1 1 2 Polarimeter 1 1 1 3 UV Spectrophotometer 1 1 1 3 Total Organic Carbon (TOC) 1 1 1 3 GC/MS 1 1 Conductivity meter 1 1 1 3 Fluorescence Spectrophotometer 1 1 Differential Scanning Calorimeter (DSC) 1 1 TG-DTA (Thermogravimetric Analysis) 1 1 X-Ray Diffraction (XRD) 1 1 Color Differential Spectrophotometer 1 1 23