□ Company Profile

□ Product List

□ History

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2007

2012

2016

2011

Anthracycline analogues Compound name SpecificationCAS No.

Amino acid analogues

■ Daunorubicin hydrochloride

■ Doxorubicin hydrochloride

■ Epirubicin hydrochloride

■ Pirarubicin＊

23541-50-6

25316-40-9

56390-09-1

72496-41-4

USP, JP, In-house

USP, JP, EP

JP, EP

JP

Vitamin D analoguesCompound name SpecificationCAS No.

■ Calcitriol

■ 25-Hydroxyvitamin D3

32222-06-3

19356-17-3

In-house

(under development)

Compound name SpecificationCAS No.

■ cis-5-Hydroxy-L-pipecolinic acid 63088-78-8 In-house

Macrolide analogueCompound name SpecificationCAS No.

■ Rapamycin (Syrolimus) Crude

■；Fermentation + Synthesis products　 ■；Fermentation Products　 ■；Bio-conversion products　 ＊；API production and Formulation

53123-88-9 In-house

[ Yatsushiro Plant ]

[ Kiyosu Plant ] [ Head office (Tokyo) ]

[ Iwata Plant ]

[ Research & Development Division ]

1-3-1 Kyobashi, Chuo-ku, Tokyo, 104-0031Tel.+81-3-6265-1761 Fax.+81-3-6265-1768http://www.microbiopharm.com

Office

Subsidiaries

MicroBiopharm Japan Co.,Ltd. (Abbreviation MBJ)

July 1st,2011

President Masanobu Suzuki

339 (As of Sep. 1st. 2016)

Mitsui&Co.,Ltd. 80% Toray Industries, Inc. 20%

USD 85 million in fiscal 2015 (USD=110 JPY)

- Establishment : In 1990- Shareholders : (China) China National Accord Medicines Co.,Ltd. (Japan) MicroBiopharm Japan Co.,Ltd. (Hong Kong) Main Life Co.,Ltd.- Business : R&D, manufacturing and sales of pharmaceutical products

Shenzhen Main Luck Pharmaceuticals Inc. (China)

Name

Date of Establishment

Representative

Total Employee

Stockholder

Sales amount

Business started

Start the production of the injectable Aclarubicin

Start the production of Daunorubicin, and injectable Pirarubicin

Start the production of Doxorubicin

Established Shenzhen Main LuckPharmaceuticals Inc. (China)

Start the production of Calcitriol

Start the production of Epirubicin

MicroBiopharm Japan was founded and started the business as the wholly-owned subsidiary of Mitsui & Co.,Ltd. by the succession of Pharmaceuticals & Chemicals businessunit of Mercian Corporation.

On January 5th, Toray Industries, Inc. acquired 20% of the capital stock of MicroBiopharm Japan.

Operation start up at Kiyosu plant in Aichi, acquired from Astellas Pharma Inc. at April 1st.

□ Our services and facilities

Laboratory scale Pilot scale Commercial scale

OH

OH

OH

NH2 . HCI

OMe H

HO

O O

O

O

O

OH

Semi-Synthesis

Fermentation

• Genetic engineering approaches• Enhancing productivity by strain improvement• Optimization of fermentation conditions• Contract research and development

• DNA sequencer• HPLC• LC-MS, LC-MS/MS• GC, GC-MS• CE• NMR

• Fermentation tanks: 3L~5kL• Filtration facilities; Filter press, Membrane filter, Centrifugal filter• Resin for purification; ~1kL • Extraction tanks• Concentration; Evaporator, Thin-film evaporator • Dryer; Freeze dryer, Spray dryer, Vacuum dryer• Others, Preparative HPLC, Isolater

• IR• X-ray diffractometer• Karl Fischer moisture titrate• Differential scanning calorimetry• Thermogravimetryetc.

• Development of fermentation and synthetic process for industrial manufacture• Manufacturing for investigational new drug

• Large fermentation tanks (60,75,100kL)• Cell filtration facilities; Oliver filter, Filter press, Belt press• Resin for purification; 8 - 10kL• Extraction tanks, Crystallization tanks • Dryer; Spray dryer

• Both small and large scale manufacturing services• GMP manufacturing• Acceptable high toxic & potent compounds

Strive to contribute to healthier and quality life of people throughout the worldq y p p gby providing pharmaceutical and other advanced products and services, y p g p ptaking advantage of our distinctive microbiological expertise and technologies.g g g p g

Fermentation

Proteinproduction

High potent

compound

- Accumulated techniques and knowledge from 50+ year experience

- FDA approved production sites

- GMP manufacturing

- Equipped with 60, 75 and 100 kL tanks

- 30+ year experience in r API commercial production

- OEM services with OEL ≧0.1μg/m3 level facilities

□Our core technology

- Experienced recombinant protein production by applying microbial host systems

-Track record of launched products in Japan

-Supports early stage development of Protein/Peptide drugs・Cytokine・Enzyme・Fab・ADC..etc.

-Commercial production with up to 3kL fermentation tanks

□ Our original Technology of R&D

By exploring and utilizing the potentials of microorganisms.MBJ meets the customer’ s needs at various stages of researches, development and commercial production.

(mg/L)

Wild Type

15-OH-CAM

Mutant

14-OH-CAM

① Drug discovery service: microbial product libraryCombining our proven microbial isolation and cultivation technology with the latest informatics makes it possible to find microorganism resources producing seed compounds of your interest.

The wild type enzymes have lower regio selectivity in hydroxylation reaction. They will give not only targeted 14-OH-Clarithromycin but also the compounds of hydroxylated in other positions. By applying our enzyme modification technology, we successfully produce the enzyme which can selectively produce the target compound with the highest selectivity.

Microbial product library(Microganisms, Extracts, Compounds)

Analysis system for microbial products Evalutation of library

Hydroxylation

Compounds difficultto develop

Improve properties 1) Water solubility enhancement2) ADMET improvement Absorption Distr ibution Metabolism Excretion Toxicity

3) Activity enhancement

CustomerMBJ

P450 library

OH

(mg/L)

1 　 2 　 3 　 4 　 5 　 6 (steps)

Product A Investigation : 6 monthx1250

Targetcompound

Byproducts

Low seletivity

Improved activity

　Enzyme evolution

Step 3 : Strain improvement (Method A)Step 4 : Strain improvement (Method B)Step 5 : Optimization of culture conditionStep 6 : Scale up

② Drug discovery service: P450 hydroxylation library

③ Productivity improvement

④ Productivity improvement

Active Active compoundscompounds

Active compounds

P450 library is a powerful screening tool, collected with Cytochrome P450 hydroxylation enzymes of various microorganisms expressed in E.coli . Our P450 library enables you to diversify and to improve properties of compounds efficiently.

We maximize the productivity of the compounds of your interest:1) Strain improvement with genetic engineering and optimization of cultivation conditions. 2) Metabolome analysis to find contributing factors for fermentation.3) Improvement of recovery and purification processes from fermentation mixture.

O

O

OH

HOH

OH

HO OCH3

H3CO

O

O

O

N

O

O

HO

O

O

OH

HOH

OH

HO OCH3

H3CO

O

O

O

N

O

O

HO

O

O

OH

HOH

OH

HO OCH3

H3CO

O

O

O

N

O

O

O

O

OH

HOH

OH

HO OCH3

H3CO

O

O

O

O

ONH

Clarithromycin (CAM)

15-OH-CAM Demethyl-CAM

14-OH-CAM

O

OH

:MBJ P450Lib.

keto

:Human P450

Hydroxylation of testosterone

Reduced byproducts