CARBOGEN AMCISCompany Overview

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Who we are

CARBOGEN AMCIS is a Swiss leading provider of drug development and commercialization services, offering Custom Development & Manufacture of APIs.

Our Mission is to help pharmaceutical industries:

Bring new generation medicines to market

Reduce time and risk associated with the drug development

Take chemistry off the critical path by providing…

…Innovative Chemistry Solutions

Locations

Dishman facilities & officesCARBOGEN AMCISLocal sales

Dishman CRAMS

AarauSwitzerlandEarly /Commercial Phase

NeulandSwitzerlandEarly / Commercial Phase

ManchesterUnited KingdomEarly / Late Phase

BubendorfSwitzerlandLate Phase / Commercial

BavlaIndiaLate Phase / Commercial

RiomFranceEarly Phase

ShanghaiChinaLate Phase / Commercial

BavlaIndiaLate Phase/ Commercial

CARBOGEN AMCIS

Company History

2006Acquisition of CARBOGEN AMCIS AG by Dishman Pharmaceuticals and Chemicals Ltd

2000Acquisition of CarboGen and AMCIS by Solutia

1990Foundation CarboGen Spin-off of the University of Zurich focused on research services and early-phase API supply

2005Investment in High Potency Facility in Bubendorf

2006Creation of CARBOGEN AMCIS AG

2007

Creation of CARBOGEN AMCIS Ltd in

Manchester, UK

2008New High Potency Facility in Ahmedabad, India

1982Foundation AMCIS joint an pharma company focused venture with on PR&D and cGMP manufacturing

2012Acquisition of CARBOGEN AMCIS SAS in Riom, France

Business Units & Company Structure

DishmanSpecialty Chemicals

Dishman Pharma Services

DishmanVitamins & Chemicals

DishmanDisinfectants

CARBOGEN AMCIS Dishman CRAMS

AarauSwitzerlandEarly/CommercialPhase

NeulandSwitzerlandEarly/Commercial Phase

ManchesterUnited KingdomEarly/Late Phase

BubendorfSwitzerlandLate Phase/Commercial

BavlaIndiaLate Phase/Commercial

RiomFranceEarly Phase

ShanghaiChinaLate Phase/Commercial

Dishman Marketable Molecule

BavlaIndiaLate Phase/Commercial

Dishman Group

Dishman Group Key Facts

Established in 1983

Public company quoted on BSE

US $300 M turnover company

Year on year growth approx. 30% since 2004

More than 1000 technical staff

Global presence – manufacturing sites

– Europe (5), – India (2), – China

ISO 9001:2000, ISO 14001:2004, OHSAS-18001:2007

Successful audit history– FDA inspected May 2006 (Bavla),

Feb 2010 (Naroda), March 2012 (Bavla, Ahmedabad)

– EDQM/TGA inspected June 2009 (Bavla), TGA:  Sept 2011 (Bavla)

– DCGI / WHO:   July 2006, Feb 2010, May 2012

– Korean FDA  Feb 2013 ( Naroda )– Accreditation as foreign

manufacturer for Japan

CARBOGEN AMCIS Key Facts

Over 20 years experience

6 sites (3 in Switzerland, 1 in the United Kingdom, 1 in France and 1 in India)

Over 200 chemists, with >40% Ph.D.

Well over 500 projects per annum

75% of projects are return customers

Over 100 projects involving production, 30% HiPo

15 Commercial products

Successful audit history

Since 2006 part of the Dishman Group

FDA, Swiss Medic, French Health Agency (ANSM), Korean FDA

Accreditation as foreign manufacturer for Japan

Our Added Value

TechnologyWe continuously invest in new technologies to stay at the forefront of chemical service providers.

ServiceOur customers benefit from the most efficient, flexible, collaborative and seamless experience possible.

PartnershipOur long-term business success is our customer’s long-term success.

Business Focus: Client Satisfaction

Sole focus on the pharmaceutical sector

Highest quality standards

Exclusive custom synthesis

No proprietary products

All compound IP belongs to the customer

Flexible and tailored solutions

Impressive in-house technologies to support different types of chemistry

Product lifecycle management through the Dishman Group

Ongoing review/implementation of new technology

– Chromatography (SMB, SFC)– Drug Product Services– High Potency– ADC

Our Services

Early PhaseProcess Research and Rapid

Supply of APIs preparedaccording to non cGMP

Late PhaseProcess Development

and cGMPManufacture

Commercial PhaseProcess Optimisation

FDA audited

Aarau (CH)50 Kg I GMP Research Preclinical Phase I Phase II Phase III

Neuland (CH)50 Kg I GMP Research Preclinical Phase I Phase II Phase III

Bubendorf (CH)200 Kg I GMP Preclinical Phase I Phase II Phase III Market

Manchester (UK)500 Kg I non GMP Research Preclinical Phase I Phase II Phase III Market

Drug Substances (DS) / API

Our High Potency Services

Early PhaseProcess Research and Rapid

Supply of APIs preparedaccording to non cGMP

Late PhaseProcess Development

and cGMPManufacture

Commercial PhaseProcess Optimisation

FDA audited

Bavla (India)200 Kg I GMP

Phase I Phase II Phase III Market

Shanghai (China)350 Kg I GMP

Phase I Phase II Phase III Market

Bubendorf (CH)75 Kg I GMP

Preclinical Phase I Phase II Phase III Market

Drug Substances (DS) / HAPI

Riom (FR)4000 vials I GMP Preclinical Phase I Phase II Phase III

Drug Products (DP)

Drug Substances (API) & Drug Products

Drug Substances / API

Process Research

Route scouting

Route development

Process Optimization

Scale-up

cGMP Manufacturing

cGMP chromatography from g to 100s Kg scale

Lifecycle Management

Drug Products

Pre-Formulation Services Formulation Services Development and optimization

of lyophilization cycles Aseptic filling Process Validation (Media Fill

Testing) Liquid forms, semi-solids and

injectables

13October 2010 - confidential

PR&D Laboratory

Regulatory Consultancy

Support and guide customers through successive phases

High quality documentation for successful due diligence

Maintain experience and avoid handovers

Support for the success of a projects for future license, sale or funding

Common & best practices

What is necessary at which stage of development

What adds additional value

Commercial Supply

Manufacture started in 1996, no product recalls

15 Commercial products

3 Oncology commercial products (parenteral application)

Multiple products undergoing validation (including lifecycle), including several HiPo

1-2 NDA filings annually

Commercial supply into the major markets (US, EU, Japan, Korea, Australia, Brazil)

Regulatory Support

CMC support for IND, IMPD, NDA and MAA

Multiple DMFs (US, EU, Japan)

CTD (Common Technical Document) format

Post-Approval Change Documentation

Type II Drug Master Files (DMFs)

European Drug Master Files (EDMFs)

Track Record of Quality

SwissMedic March 2012 – Aarau, Neuland March 2012 – Bubendorf No major findings

FDA September 2011 – Bubendorf No 483’s noted on this or any

previous FDA audit

ANSM (French Health Agency) May 2012 – Riom No major findings 2013 – Korean FDA 

Japan

Accreditation as foreign manufacturer for Japan since 2009

Customers

>25 different customer audits annually

At least 4 different (Top 10 Pharma) customer ESH audits annually

Lifecycle Management

Track record of successful technology transfer of processes to Dishman Group

– >15 processes transferred to date including RSM, intermediates and launched APIs

Continuous monitoring of process performance

Continuous evaluation and implementation of process improvements (Lean and 6-sigma techniques)

In depth experience of managing the post-approval change processes of all main regulatory bodies

Continuous monitoring of the changing requirements

Transition management to generic supply

Experience of filing CEPs at the EDQM

Quality Assurance Strategy

“Fit for Purpose” supply chain

Strategy agreed up front

Classical & Lifecycle validation approach according to FDA guideline

Expedite filing through registration batch approach

Quality by Design approach

Fully compliant with ICH-Q8,9, 10 & 11

PAR studies

Optimisation by statistical DoE as required

Product quality risk assessment

Analytical Services Overview

• Structure Elucidation• Absolute Configuration• Solubility Profile• Salt Screening• Polymorphism• Particle Sizing• Compatibility• Impurity Profiling• Solid State Characterization

• Drug Product Characterization

• Method Development• Inpurity Tracking• Method Verification• Specification Development• Specification Justification• Method Validation • Raw Material

• IPC • API

• Release Analysis• Method Transfer• Reference Standards

• ICH Stability• Stress Stability• Drug Substance Stability• Drug Product Stability• Degradation Profiling

Control StabilityCharacterization

Equipment for Drug Products

GMP Production

5 Isolators

Laminar Flow Hoods

1 GMP Freeze Dryer Terruzzi 1.2 m² CIP+SIP

1 Autoclave

1 Dry Heat Oven

Dedicated Formulation and Pre-formulation Labs

Solid Forms (oral drugs)

Liquid Forms (injectables)

Stability Chambers

Safe location in Switzerland

Fully GMP validated and mapped

Operational at ICH conditions

Stringent IQ, OQ, and PQ

Routing calibration

Continuous monitored (24/7)

Monitoring systems FDA compliant (21CFR Part 11)

Real-time access to data via LIMS-System

Equipment for API Manufacturing

70 general-purpose reactors (from 6 L to 4500 L)

5 cryogenic reactors (40 L to 3000 L)

High temp reactor (200 L)

High pressure autoclaves (range of scales)

Hastelloy filter dryers (from 0.25 to 1 m2)

Temp range: -100°C to +160°C

Pressure range: 1 mbar to 25 bar

Milling / Micronization

Milling Equipment

Site Type Scale Sieve Size (mm) GMP Category

Lab

NE IKA MF 10 basic 5 – 500 g 0.25 – 3   0 - II

AA Jetpharma MC-one 0.5 – 500 g N/A   0 - II

Pilot / Manufactutring

AA Frewitt TC-150 1 – 12 Kg 0.5 / 1 / 5 0 - I

BU Frewitt 100 Kg 1 0 - I

NE Quadro Comil U10 1 – 12 Kg 0.279 / 0.6 / 1 / 4.7 0 - I

AA Jetpharma MC-50 0.5 – 2 Kg N/A 0 - I

Wet Milling Equipment

* Aarau, AA (CH): up to Category II, Neuland, NE (CH): up to category II, Bubendorf, BU(CH): up to category IV; Bavla (IN): up to category IV

Site TypeLoop

Milling Volume (L)

Transfer Milling

Volume (L)

Feed (L/hr)

d90 (µm) GMP Category

Lab

Mobile* IKA Magic Lab 0.5 - 5 0.5 - 5 ≤ 120 20 – 50 0 - IV

Mobile* IKA Magic Lab 0.5 - 5 0.5 - 5 ≤ 120 20 – 50 0 - IV

Pilot / Manufacturing

Mobile*IKA Process Pilot 2000/4

10 - 100 100 - 1000 120 -500 20 – 50 0 - IV

Mobile*IKA Process Pilot 2000/4 Atex

10 - 100 100 - 1000 120 -500 20 – 50 0 - IV

Mobile* IKA DR 2000/5 100 - 400 400 - 5000 ~ 2500 20 – 50 0 - IV

Freeze and Spray Drying

Site Type Productivity Range

Ice Capacity

Condenser T (°C)

# Trays GMP Category

Lab

BU (mobile)

Lyo Zirbus 2x3x3/5

max 300 g/run *

max 4 Kg/run - 80°C 3 (2 L) 0 - IV

Riom Telstar Lyobeta 20 (1)

7.2 L/run (bulk)

max 12 Kg/run - 80°C 4 + 1 0 - IV

NEBüchi Mini Spray Dryer B-290

up to 100 g/h*

n.a. -10°C n.a. 0 - II

Pilot / Manufacturing

AA Telstar Lyobeta 20 (2)

max 1 Kg/run*

max 30 Kg/run - 80°C 4 + 1 0 - II

Riom Terruzzi (3) 14.4 L /run (bulk)

max 30 Kg/run - 80°C 4 + 1 0 - IV

* (Solutions: 10% w/w)(1) Max 2'480 vials (2R) - Automatic stoppering possible(2) Automatic stoppering possible(3) Max 3'952 vials (2R) - Automatic stoppering possible

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Chromatography Services g to Kg

200-2000 g/d

SMB Licosep10-50Binary

Separationsracemates

1-5 kg/d

Flash Chromatography

Biotage 400 LSystem

Multi-componentseparations

20-350 g/d

2x PreparativeHPLC

Knauer + Dan-process

10 cm IDColumns

Multi-componentseparations

500-10000 g/d

Preparative MPLC

Verdot/ArmenLarge-scale

Normal phase

100-1500 g/d

Preparative HPLCNovasep

20 cm ID column5 and 15 cm ID columns for HiPoMulti-component

separations

0.4-30 kg/d

Preparative HPLC

Novasep30cm and 45cm

ID columnMulti-component

separations

August 2013 - confidential

High Potency Capabilities

Highly Potent APIs for (pre)clinical trials and commercial use

Pilot PlantManufacturing

Facility

Up to 1600 L

Laboratories

Up to 10 L

OEL<0.1g/m3

Up to Category IV

Kilo-Scale Manufacturing

Facility

Up to 250 L

Large-ScaleManufacturing

Facility

Up to 1600 L

Large-ScaleManufacturing

Facility

Up to 8000 L

BubendorfSwitzerland

BavlaIndia

ShanghaiChina

OEL<0.1g/m3

Up to Category IV Up to Category III

OEL<0.1g/m3

Up to Category IV Up to Category III

OEL<10g/m3

RiomFrance

Aseptic Filling

Up to 4000 vials

OEL<1g/m3

Up to Category IV

OEL1-100g/m3

HiPo Manufacturing – Cat III

28October 2010 - confidential

HiPo Analytical Capabilities

Categorisation

Criteria Category 0 Category I Category II Category III Category IV

Potency (1) > 500 > 100 100 – 10 10 – 0.1 < 0.1

OEL range (2) 5000 – 1000 1000 – 100 100 – 10 10 – 1 1 – 0.05 *

Toxicity oral LD50

(3)

> 1000 1000 – 300 300 – 50 50 – 5 < 5

NOAEL (4) > 100 100 – 10 10 – 1 1 – 0.1 < 0.1

Acute adverse

effects

None Slight Moderate;

reversible

Moderate – severe;

reversible

Severe; irreversible

Chronic adverse

effects

None None Slight – moderate Moderate;

irreversible

Severe; irreversible

– lethal

Genotoxicity None None None – (+) Ames

Test

(+) in a battery of

studies

(+) in a battery of

studies

(1) Dose [mg/d] (2) g/m3as 8h – TWA (3) mg/kg, rat (4) 28d, mg/Kg, oral rat

* Standard value based on industrial hygiene data. Lower equipment or process specific values possible, depending on additional measures

HiPo

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Project Management Communication

Steering Committee

Weekly Report

Regular Phone Conference Technical Visits

Management

Customer

Project Leader

Chemists

Purchasing Ad hoc communication

Management

CARBOGEN AMCIS

Project Leader

Chemists

Sales

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Flexible Approach

Open Business Model

One-off ProjectFrameworkAgreement

FTE Agreement Manufacturing

• Deliverables• Project budgets• Payment terms• Termination

• Overall budget• Payment terms• Termination

• FTE Rates• Resource level• Payment terms• Renewal• Termination

• Budget ($/Kg)• Payment terms• Forecasting• Termination

Project

Pro

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CARBOGEN AMCIS Advantages

Long track record in handling complex and long synthetic processes

500+ projects in 2011

100+ projects involving production (30% of which are HiPo)

126 standalone analytical projects

50+ R&D projects

40+ Stability Studies

20+ Chromatography projects

Phase appropriate development

Robust, reproducible & industry-scalable process

Experience from a broad customer base

Comprehensive package Within available budget &

timelines Tailored based on customer

preferences One-stop-shop to limit the

number of suppliers to be managed for drug products and substances

Commercial track records Lifecycle management High quality infrastructure

(nonGMP, cGMP) Flawless audit history

What‘s New ? – Bubendorf, Switzerland

~ 4 Mio USD invested

cGMP clean room for antibody drug conjugates (ADCs)

Sterile room (grade D/ C)

OEL <1 µg/m3 8h-TWA

Pressure Cascade (+30 Pa, +15 Pa, 0 Pa, -15 Pa)

Equipment Available:

Isolators, Barrier Systems and Walk-in fume hoods

Bio-safety cabinets (grade C)

Dry oven sterilizer and autoclave for sterilization

~ 1 Mio USD invested

cGMP suite for High Potency Chromatography

Equipment Available:

3 Walk-in-Barrier Hoods HPLC 10 and 15 cm ID column

50 - 500 g/day

1000 ml/min at 70 bar

What‘s New ? – Riom, France

Investment: ~ $950,000 USD

Implementation of a new VHP (Vaporized Hydrogen Peroxide) disinfection system

Acquisition of 2 new aseptic filling isolators

New Bag-In/Bag-Out system for HEPA filters exchange

Increased level of sterility assurance in terms of disinfection, air-tightness and air flow

Grade A (ISO 4.8) compliant throughout the entire process

What‘s New ? – Bavla, India

New High Potency Kilo-lab (~ 110 m2 floor space)

Class 100.000

Separate material and personnel airlocks

Negative Pressure Cascade among corridor/airlocks/operational areas(+15 Pa, 0 Pa, -15 Pa)

HEPA Filters for air in and out (AHU single pass)

[8hr TWA]: 50 ng/m³ > OEL < 1 μg/m³

3 reactors (glass lined and SS) equipped with charging isolators

1 Agitated Nutsche Filter Drier (ANFD) equipped with discharging isolator

Thank you!

Name Surname, Ph.D.TitleTel: xx-xxx-xxx-xxxCARBOGEN AMCIS Hauptstrasse 171CH-4416 BubendorfSwitzerland