Hongene Biotechnology USA, Inc

Hongene Biotechnology USA, Inc., 3131 RDU Center Dr. Ste 140, Morrisville, NC 27560, Email: [email protected]

Hongene Biotechnology USA, Inc.

Leading Exper;se in Nucleosides, Nucleo;des, and Phosphoramidites

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§  Company General Introduc;on

§  R&D/Manufacturing Facili;es (M1 and M2)

§  Research and Development Capabili;es

§  Project Management

§  Quality System

§  Analy;cal/ QC laboratories

§  Technologies (tradi;onal nucleoside chemistry and enzyma;c bioconversions)

§  Intellectual property protec;on

§  Products and Services

§  Summary – why Hongene (high quality and low cost)

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Overview


Corpora;on – Interna;onal Presence

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§  Hongene Biotechnology Ltd, Shanghai, China

Registered in Hong Kong, Privately held Headquarter located in Shanghai

§  Hongene Biotechnology USA Inc.

3131 RDU Center Dr., Suite 140, Morrisville, NC 27560 Tel: 001-‐919-‐371-‐4711; Mobile: 001-‐919-‐780-‐8685

§  株式会社Hongene Japan

3-‐18-‐9, Sendagaya, Shibuya-‐ku, Tokyo, 151-‐0051 Tel: 0081-‐3-‐5786-‐3515 Fax: 0081-‐3-‐3470-‐3061


§  A US-‐based biotechnology company, incorporated in Research Triangle Park, North Carolina

§  A subsidiary of Hongene Biotechnology Limited, located in Shanghai, China

§  Focus on new product development, process con;nuous improvement of nucleoside, nucleo;de, and phosphoramidite products

§  Provide Quality and Compliance stewardship

§  Decade of experience working and serving pharmaceu;cal and biotech industries

§  Primary customers include world-‐class pharmaceu;cals, biotechs, fine chemicals and catalog companies mainly in US and Europe

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General Introduc;on



§  Registered in Hong Kong in 1998, headquartered in Biotech Park, Shanghai

§  Incubated in Shanghai Ins;tute for Biological Sciences, Chinese Academy of Science (CAS)

§  Technologies -‐ chemical synthesis, enzyma;c bioconversion, purifica;on and crystalliza;on technologies for nucleoside, nucleo;de, and phosphoramidite products

§  Broad products lines with more than 350+ products in-‐house

§  Offers high quality products, CRO/CMO services and custom synthesis services with compe;;ve price

§  Best customer sa;sfactory survey (product quality, delivery ;me and overall services) from several world well-‐known companies

§  Two R&D/manufacturing facili;es: M1 is ISO 9001 cer;fied; M2 is GMP standard (total commissioned in February 2013) and will be GMP cer;fied by SFDA in 2014

§  Currently 90+ employees with 95% holding Bachelor degrees or advanced degrees

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Hongene Biotech Ltd. (Shanghai)


§  Headquarter located at Shanghai Ins;tute for Biological Sciences, Chinese Academy of Science (CAS)

§  Two (2) R&D laboratories (enzyme research and scale up) located at headquarter

§  Two R&D/manufacturing facili;es

1)  Facility one M1: located 40 km from the headquarter, include four (4) R&D laboratories; one (1) QC lab; and two (2) manufacturing buildings (one for nucleosides and nucleo;des manufacturing and one for phosphoramidites manufacturing)

2)  Facility two M2 : located 15 km from the headquarter, include four (4) R&D laboratories, one (1) analy;cal research and development and QC lab; and two (2) manufacturing buildings (one for nucleosides and nucleo;des manufacturing and one for phosphoramidites manufacturing); and QA offices.

§  R&D products from mg to hundred grams

§  Pilot/commercial scale products from kgs to metric tons

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Facili;es in Shanghai

Hongene Biotechnology USA, Inc., 3131 RDU Center Dr. Ste 140, Morrisville, NC 27560, Email: [email protected] 7

A: Headquarter of Hongene Biotech Ltd (Marketing/sales and Finance) B: R&D/manufacturing facility one M1 C: R&D/manufacturing facility two M2 (commissioned in February, 2013)

Map of Shanghai City

Pudong Int’l Airport


R&D/Manufacturing One M1

§  Two Produc;on buildings §  Nucleosides and nucleo;des §  Phosphoramidites

§  35,000 sf produc;on floor including 4,000 sf independent building for phosphoramidites pilot/manufacturing

§  Four (4) Research and development laboratories suppor;ng pilot/manufacturing ac;vi;es §  Reactors:

§  3000 L (1) jacketed glass-‐lined; 1000 L (1) jacketed glass-‐lined; 500 L (1) jacketed glass-‐lined; §  200 L (2) jacketed glass-‐lined §  200 L (1) S-‐S jacketed hydrogenator §  Mul;ple 50 L – 100 L other jacketed reactors

§  Independent phosphoramidites pilot/produc;on building with 500 kg phosphoramidites annual capability

§  HEPA air handling system for phosphoramidites pilot/produc;on building to prevent from cross contamina;ons

§  Two RO water purifica;on systems with 3 T/h capacity


§  Clean room (class 100k ) §  Produc;on area 2,200 sf §  Dryer, crystallizer, milling machine, mixers and packing devices §  Lypholizer

§  Large pilot/produc;on purifica;on columns (15) §  1300 L (3); 400 L (4); 270 L (1); 150 L (2); §  Others are 50 L to 100 L §  All columns are custom-‐designed and built

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R&D/Manufacturing One M1 (cont’d)


§  Ground-‐breaking in October 2011 and total commissioned in February, 2013

§  15 km away from the headquarter §  About 100,000 sf total produc;on area for nucleosides and nucleo;des

pilot/commercial manufacturing (nucleoside chemistry, workups, and column purifica;on), as well as phosphoramidite produc;on area

§  Four R&D Laboratories (4) suppor;ng pilot/produc;on ac;vi;es §  Hold up to 100 – 120 employees §  Independent phosphoramidite pilot/produc;on building with 4,000 kg

annual capacity

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R&D/Manufacturing Two M2


§  On-‐site waste water treatment system §  Reactors (15) from 200 L to 5000 L §  Large produc;on purifica;on column (15) from 200L to 1300L §  Two clean rooms (class 100k) with several crystallizers, dryers,

milling, lypholizers, and packaging devices §  HEPA air handling system for all buildings

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R&D/Manufacturing Two M2 (cont’d)


The front view of M2

The back view of M2

R&D/Manufacturing Two M2 (cont’d)


§  A total of ten (10) R&D laboratories (including 4 walk-‐in hood laboratories) with a total of 30+ scien;sts at Hongene Biotech

§  Eight (8) R&D laboratories focus on nucleoside, nucleo;de, and phosphoramidite studies and two (2) R&D laboratories focus on enzyme studies and bioconversion

§  Scien;fic advisors §  Three full-‐;me senior professors re;ed from Shanghai Ins;tute of Organic

Chemistry, Chinese Academy of Science (CAS) §  Each professor has more than 40 years experience of nucleoside, nucleo;de,

and enzyme studies

§  R&D laboratories feature typical nucleoside and nucleo;de laboratory equipment as well as some modern analy;cal equipment such as HPLC, GC, LC/MS, prep-‐LC and etc.

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R&D Capabili;es


§  Applied to CRO/CMO and custom synthesis projects §  A project manager is assigned to each project, the

scope of the project incudes, not limited to, budget, ;meline, IP, reports and etc.

§  Weekly or periodical project update via emails, teleconferences (i.e. using WebEx tool) and onsite visit

§  Hongene to write periodical and project-‐end development report or a campaign report summarizing the campaign, improvements, all analy;cal data, and etc.

Project Management

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§  Quality system has the func;ons of Quality Assurance, Quality Control and Regulatory/IP services

§  Manufacturing facility M1 is ISO9001 cer;fied; Manufacturing facility M2 was build per GMP standard, and will be GMP cer;fied by SFDA in 2014

§  Fully loaded Analy;cal/QC lab and comprehensive documenta;on system

§  Mul;ple quality audits and vendor qualifica;on audits from companies in US and Europe per year

§  Periodical internal quality audit programs

§  Best customer sa;sfactory survey from several world well-‐known companies (98/100 perfect score from the quality, delivery ;me, documenta;on, and services)

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Quality System


Surveys From Two Major US Customers


§  Fully loaded Analy;cal/QC laboratory performs all product release tes;ngs except NMR (31PNMR, 13CNMR and 1HNMR done in CAS center)

§  A new NMR will be installed in new facility M2 in 2013. §  Analy;cal method research and development §  Method valida;on and transfer §  Stability studies including accelerated stability studies for all in-‐house

products and the custom synthesis products §  Typical analy;cal instruments are HPLC for product ID, purity and assay;

LC/MS for molecular mass; GC for residual solvents; UV for purity; KF for moisture content; AA for heavy metal analysis; Turbidimeter for solu;on clarity; bacterial endotoxin analysis; and etc.

§  Impurity isola;on, synthesis and structure elucida;on §  Provides formal CoA for each lot of product manufactured

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Analy;cal/QC lab


Impurity Profile Strategy

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§  Impurity (critical impurity) level: Ø  >= 0.1%, the impurity will be identified; reference impurity

will be isolated or synthesized Ø  >=0.05, the impurity will be identified

§  Raw Material Control Ø  Extensive analysis of raw material Ø  Impurity limit in raw material

§  Process Control Ø  In process testing Ø  In process limit of critical and non critical impurity


Manufacturing Control

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§  Devia;on inves;ga;on system Ø  Approved by Supervisor

Ø  Approved by QA

§  Document change control

§  Defined in process control

§  Calibra;on and maintenance program

§  Non Conforming Material (NCM) or OOS procedure

§  Equipment change control


FULLY INTEGRATED SUPPLY CHAIN

Key Raw

Material

Phosphoramidites

High Quality Nucleosides

PNS (Base Protected Nucleosides)

PNS (DMT- Protected Nucleosides)

Hongene Biotechnology Ltd. Confidential


Supply Chain Strategy

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§  Integrated all key materials strategy

Ø  Nucleosides, PNS, and Phos reagent (in process)

Ø  Capacity to support multi ton quantity

§  All raw material from Chinese source

§  Minimum two qualified suppliers for each material

Ø  Periodic suppliers audit

Ø  Supplier qualification and approval

Ø  Change control notification and approval


OOH

R2 R1

Base1O

OH

R2 R1

Base2

Chemical Synthesis (traditional nucleoside chemistry)

Enzymatic Bioconversion (green chemistry)

+ Base2

Enzymes

State-of-the-art Technology

+

Base

O Base

R2 R1

R3OO OR4

R2 R1

R3O

** Hongene has its own IP of enzymatic bioconversion technologies for more than 60% of its own in-house products or processes


Case Study -‐dCMP

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§  Key to the sustainable growth to Hongene and to the clients

§  Internal IP procedures and training programs §  IP contracts such as CDA to protect both Hongene’s IP

and clients’ IP §  For IP protected products, Hongene needs legal

permission from the IP owner or the end user who issues a legal statement

§  Hongene reserve rights to provide Hongene’s IP for regulatory purpose

Intellectual Property (IP)

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§  Product categories (more than 350 products in house) §  Nucleosides §  Nucleo;des §  Arabinonucleosides and Arabinonucleo;des §  Phosphoramidites

§  Offers CRO/CMO and custom synthesis services for nucleosides, nucleo;des and phosphoramidites

§  All raw materials are made in China and all major raw materials are made in house to ensure the quality and efficient supply

§  Free samples are available for some selected products

§  Guaranteed high quality to meet customer’s need with comple;ve price and the best lead-‐;me

§  Most products are made via chemical synthesis and/or enzyma;c bioconversion

§  Non-‐animal/human origin policy for all incoming raw materials and products on site

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Products and Services


Commercial API Products

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Cat. No. Abbreviation Full Name Commercial Name CAS No. Structure Grade Therapeutical class

A1-001 Ara-A 9-β-D-Arabinofuranosyladenine Vidarabine 5536-17-4 USP Antiviral

D5-015 5-F-dU 5-Fluoro-2'-deoxyuridine Floxuridine 50-91-9 USP Cancer

A3-001 Ara-C 1-β-D-Arabinofuranosylcytosine Cytarabine 147-94-4 USP Cancer

D5-006 5-I-dU 5-Iodo-2'-deoxyuridine Idoxuridine 54-42-2 USP Antiviral

A1-004 2-F-Ara-AMP2-Fluoro-9-β-arabinofuranosyladenine 5'-monophosphate

Fludarabine (Fludara) 75607-67-9 USP Cancer

N

NH

O

O

O

HOCH2

OH

F

N

N

O

NH2

OHOCH2

OH

OH

N

NH

O

O

O

HOCH2

OH

I

N

N N

N

NH2

F

POH

O

OH

OHO

O

OH

N

N N

N

NH2

OHOCH2

OH

OH

Note: Hongene also offers intermediates of those APIs:


2’-Deoxynucleosides 2’-Deoxyadenosine (2’-dA)☆

2’-Deoxyguanosine (2’-dG)☆

2’-Deoxycytidine (2’-dC)☆

2'-Deoxycytidine hydrochloride (2’-dC.HCl)☆

5-Methyl-2'-deoxycytidine (5-Me-dC)※ ☆

2’-Deoxyinosine (2’-dI)☆

2’-Deoxyuridine (2’-dU)☆※

Thymidine (dT)※

2,6-Diaminopurine-2’-deoxyriboside ☆Bioconversion ※Chemical Synthesis

HPLC≥99.0％

N

N

O

O

HOCH2

OH

NH2

.HCl

Anomer: None Detected


Product Series 1 -‐ Nucleosides


2’-F-deoxynucleosides

2’-Fluoro-2’-deoxyadenosine (2'-F-dA)☆

2'-Fluoro-2'-deoxycytidine (2'-F-dC)※

2’-Fluoro-2’-deoxyguanosine (2'-F-dG)☆

2'-Fluoro-2'-deoxyuridine (2'-F-dU)※

5-Methyl-2'-Fluoro-2'-deoxyuridine (2'-F-dT)※

2'-Fluoro-2'-deoxyinosine (2'-F-dI)☆

More · · · · · · ☆Bioconversion ※Chemical Synthesis

N

N N

N

O

OH

NH2

HOCH2

F

HPLC≥99.0％

Product Series 1 – Nucleosides (cont’d)


§  Nucleosides Featured Products

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2’-‐OMe-‐nucleosides

2’-‐MOE-‐nucleosides*

* For IP eligible, end-‐users only.




2’-‐NH2-‐deoxynucleosides

3’-‐NH2-‐2’,3’-‐dideoxynucleosides*

3’-‐Azido-‐2’,3’-‐dideoxynucleosides




§  Nucleosides Featured Products Halogen-‐nucleosides Base Protected Nucleosides




Locked Nucleic Acid (LNA) *

* For IP eligible, end-‐users only.

DMT Protected Nucleosides


Product Series 2 – Nucleo;des

dNMP Products

dNDP Products

§  Deoxynucleo;des Series Featured Products (dNMP, dNDP, dNTP):


Product Series 2 – Nucleo;des (cont’d)

§  Deoxynucleo;des Series Featured Products (dNMP, dNDP, dNTP):

dNTP Powder

dNTP Solu;on Products

Modified dNTP Products



§  Ribonucleo;des Series Featured Products (NMP*, NDP, NTP):

NDP Powder Products

NTP Powder Products

* Most NMP products are purchased in raw and then purified in house for quality purpose.



§  Ribonucleo;des Series Featured Products (NMP*, NDP, NTP):

NTP Solu;on Products

Modified NTP Products

* Most NMP products are purchased in raw and then purified in house for beoer quality control.


Product Series 3 – Arabinonucleosides and Arabinonucleo;des

Ara-A (9-β-D-Arabinofuranosyl-Adenine) Ara-C Ara-G Ara-U

N

N N

N

NH2

OHOCH2OH

OH

§  Arabinonucleosides Featured Products

Ara-AMP Ara-CMP 2-F-Ara-AMP

§  Arabinonucleo;des Featured Products


Product Series 4 – Phosphoramidites

§  Phosphoramidites Featured Products

3’-‐NH-‐2’,3’-‐dideoxynucleosides Phosphoramidites*

2’-‐Fluoro-‐Deoxynucleosides Phosphoramidites


Product Series 4 – Phosphoramidites (Cont’d)

§  Phosphoramidites Featured Products

2’-‐O-‐Methyl-‐Nucleosides Phosphoramidites

Other Modified Phosphoramidites






Linker Phosphoramidite TFA-C6-amine-linker Phosphoramidite

Tr-C6-amine-linker Phosphoramidite

MMT-C6-amine-linker Phosphoramidite

DMT-C6-amine-linker Phosphoramidite

Spacer Phosphoramidite C3

Spacer Phosphoramidite 18

UniCap Phosphoramidite �

More · · · · · ·

MMT-C6-amine-linker Phosphoramidite

UniCap Phosphoramidite



High Quality Low Cost Leader

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§  Enzymatic bioconversion technology (green chemistry) and manufacturing process and control strategies

§  High quality starting materials and intermediates §  Manufacturing process control §  Impurity profile control strategies §  Fully Integrated Supply Chain §  Key raw material - Phos reagent, DMT-Cl, and etc §  Capacity

Ø  Multi tons capacity to support your need from development to product launch

Ø  Space for further expansion, if needed

§  Reduced Labor & Operation Cost Ø  Manufacturing of all precursors and finished good in China


Q&A

Thanks for mee;ng me today.

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For any ques;ons or inquiries, please contact Cur;s Cui President Hongene Biotechnology USA, Inc. 3131 RDU Center Drive, Suite 140 Morrisville, NC 27560 Office: (919)371-‐4711 Mobile: (919)780-‐8685 Email: cur;[email protected] or [email protected]

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Leading Exper;se in Nucleosides, Nucleo;des and Phosphoramidites !

Business

Hongene Biotechnology USA, Inc