Transcript Outsourcing API Manufacture to India & China A Suppliers Perspective

CARBOGEN AMCIS
Company Overview
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
2
Locations
Dishman facilities & offices
CARBOGEN AMCIS
Local sales
CARBOGEN AMCIS
Dishman CRAMS
Manchester
United Kingdom
Early / Late Phase
Neuland
Switzerland
Early / Commercial Phase
Bubendorf
Switzerland
Late Phase / Commercial
Riom
France
Early Phase
Aarau
Switzerland
Early /Commercial Phase
Bavla
India
Late Phase/ Commercial
Bavla
India
Late Phase / Commercial
Shanghai
China
Late Phase / Commercial
Company History
2012
Acquisition of
CARBOGEN AMCIS SAS in
Riom, France
2005
2007
Investment in
High Potency
Facility in Bubendorf
Creation of CARBOGEN
AMCIS Ltd in
Manchester, UK
1990
2006
Foundation CarboGen
Spin-off of the University
of Zurich focused on
research services and
early-phase API supply
Creation of
CARBOGEN AMCIS AG
2008
2006
Acquisition of CARBOGEN AMCIS
AG by Dishman Pharmaceuticals
and Chemicals Ltd
2000
1982
Foundation AMCIS
joint an pharma company
focused venture with on
PR&D and cGMP
manufacturing
Acquisition of CarboGen
and AMCIS by Solutia
New High Potency
Facility in
Ahmedabad, India
Business Units & Company Structure
Dishman Group
Dishman Pharma Services
Dishman Marketable Molecule
Dishman
Specialty
Chemicals
Dishman
Vitamins &
Chemicals
CARBOGEN AMCIS
Manchester
United Kingdom
Early/Late Phase
Riom
France
Early Phase
Dishman
Disinfectants
Dishman CRAMS
Neuland
Switzerland
Early/Commercial
Phase
Bubendorf
Switzerland
Late Phase/
Commercial
Aarau
Switzerland
Early/Commercial
Phase
Bavla
India
Late Phase/
Commercial
Bavla
India
Late Phase/
Commercial
Shanghai
China
Late Phase/
Commercial
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, OHSAS18001:2007
 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
Technology
We continuously invest in new technologies to stay at the
forefront of chemical service providers.
Service
Our customers benefit from the most efficient, flexible,
collaborative and seamless experience possible.
Partnership
Our long-term business success is our customer’s longterm 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 Phase
Late Phase
Commercial Phase
Process Research and Rapid
Supply of APIs prepared
according to non cGMP
Process Development
and cGMP
Manufacture
Process Optimisation
FDA audited
Drug Substances (DS) / API
Manchester (UK)
500 Kg I non GMP
Research
Preclinical
Phase I
Phase II
Phase III
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
Preclinical
Phase I
Phase II
Phase III
Bubendorf (CH)
200 Kg I GMP
Market
Market
Our High Potency Services
Early Phase
Late Phase
Commercial Phase
Process Research and Rapid
Supply of APIs prepared
according to non cGMP
Process Development
and cGMP
Manufacture
Process Optimisation
FDA audited
Drug Products (DP)
Riom (FR)
4000 vials I GMP
Preclinical
Phase I
Phase II
Phase III
Preclinical
Phase I
Phase II
Phase III
Market
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
Drug Substances (DS) / HAPI
Bubendorf (CH)
75 Kg I GMP
Drug Substances (API) & Drug Products
Drug Substances / API
Drug Products
 Process Research
 Pre-Formulation Services
 Route scouting
 Formulation Services
 Route development
 Development and optimization
of lyophilization cycles
 Process Optimization
 Aseptic filling
 Scale-up
 Process Validation (Media Fill
Testing)
 cGMP Manufacturing
 cGMP chromatography from g
to 100s Kg scale
 Lifecycle Management
 Liquid forms, semi-solids and
injectables
PR&D Laboratory
October 2010 - confidential
13
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
Japan
 March 2012 – Aarau, Neuland
 Accreditation as foreign
manufacturer for Japan since
2009
 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
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
 Quality by Design approach
 Strategy agreed up front
 Fully compliant with ICH-Q8,9,
10 & 11
 Classical & Lifecycle validation
approach according to FDA
guideline
 Expedite filing through
registration batch approach
 PAR studies
 Optimisation by statistical DoE
as required
 Product quality risk
assessment
Analytical Services Overview
Characterization
• Structure Elucidation
• Absolute Configuration
• Solubility Profile
• Salt Screening
• Polymorphism
• Particle Sizing
• Compatibility
• Impurity Profiling
• Solid State
Characterization
• Drug Product
Characterization
Control
• Method Development
• Inpurity Tracking
• Method Verification
• Specification Development
• Specification Justification
• Method Validation
• Raw Material
• IPC
• API
• Release Analysis
• Method Transfer
• Reference Standards
Stability
• ICH Stability
• Stress Stability
• Drug Substance Stability
• Drug Product Stability
• Degradation Profiling
Equipment for Drug Products
GMP Production
Stability Chambers
 5 Isolators
 Safe location in Switzerland
 Laminar Flow Hoods
 Fully GMP validated and
mapped
 1 GMP Freeze Dryer Terruzzi
1.2 m² CIP+SIP
 Operational at ICH conditions
 1 Autoclave
 Stringent IQ, OQ, and PQ
 1 Dry Heat Oven
 Routing calibration
 Continuous monitored (24/7)
Dedicated Formulation and
Pre-formulation Labs
 Monitoring systems FDA
compliant (21CFR Part 11)
 Solid Forms (oral drugs)
 Real-time access to data via
LIMS-System
 Liquid Forms (injectables)
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
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
AA
Frewitt TC-150
1 – 12 Kg
0.5 / 1 / 5
a
0-I
BU
Frewitt
100 Kg
1
a
0-I
NE
Quadro Comil U10
1 – 12 Kg
0.279 / 0.6 / 1 / 4.7
a
0-I
AA
Jetpharma MC-50
0.5 – 2 Kg
N/A
a
0-I
Lab
Pilot /
Manufactutring
Wet Milling Equipment
Site
Type
Loop
Milling
Volume (L)
Transfer
Milling
Volume (L)
Feed
(L/hr)
d90
(µm)
GMP
Category
Mobile*
IKA Magic
Lab
0.5 - 5
0.5 - 5
≤ 120
20 – 50
a
0 - IV
Mobile*
IKA Magic
Lab
0.5 - 5
0.5 - 5
≤ 120
20 – 50
a
0 - IV
Mobile*
IKA Process
Pilot
2000/4
10 - 100
100 - 1000
120 -500
20 – 50
a
0 - IV
Mobile*
IKA Process
Pilot
2000/4 Atex
10 - 100
100 - 1000
120 -500
20 – 50
a
0 - IV
Mobile*
IKA DR
2000/5
100 - 400
400 - 5000
~ 2500
20 – 50
a
0 - IV
Lab
Pilot /
Manufacturing
* 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
Freeze and Spray Drying
Site
Lab
Type
Productivity
Range
Ice
Capacity
Condenser
T (°C)
#
Trays
GMP
a
Category
BU
(mobile)
Lyo Zirbus
2x3x3/5
max 300
g/run *
max 4
Kg/run
- 80°C
3 (2 L)
Riom
Telstar
Lyobeta 20 (1)
7.2 L/run
(bulk)
max 12
Kg/run
- 80°C
4+1
0 - IV
NE
Büchi Mini
Spray Dryer B290
up to 100
g/h*
n.a.
-10°C
n.a.
0 - II
AA
Telstar
Lyobeta 20 (2)
max 1
Kg/run*
max 30
Kg/run
- 80°C
4+1
a
0 - II
Riom
Terruzzi (3)
14.4 L /run
(bulk)
max 30
Kg/run
- 80°C
4+1
a
0 - IV
0 - IV
Pilot /
Manufacturing
* (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
Chromatography Services g to Kg
SMB Licosep
10-50
Binary
Separations
racemates
Flash
Chromatography
Biotage 400 L
System
Multi-component
separations
200-2000 g/d
1-5 kg/d
August 2013 - confidential
2x Preparative
HPLC
Knauer +
Dan-process
10 cm ID
Columns
Multi-component
separations
Preparative HPLC
Novasep
20 cm ID column
5 and 15 cm ID
columns for HiPo
Multi-component
separations
20-350 g/d
100-1500 g/d
25
Preparative
HPLC
Novasep
30cm and 45cm
ID column
Multi-component
separations
Preparative
MPLC
Verdot/Armen
Large-scale
Normal phase
0.4-30 kg/d 500-10000 g/d
High Potency Capabilities
Highly Potent APIs for (pre)clinical trials and commercial use
Riom
France
Aseptic
Filling
Bubendorf
Switzerland
Laboratories
Up to 10 L
Bavla
India
Shanghai
China
Kilo-Scale
Manufacturing
Facility
Pilot Plant
Manufacturing
Facility
Large-Scale
Manufacturing
Facility
Large-Scale
Manufacturing
Facility
Up to 250 L
Up to 1600 L
Up to 1600 L
Up to 8000 L
Up to 4000 vials
OEL<1g/m3
OEL<0.1g/m3
OEL<0.1g/m3
OEL<10g/m3
OEL<0.1g/m3
OEL1-100g/m3
Up to Category IV
Up to Category IV
Up to Category IV
Up to Category III
Up to Category IV
Up to Category III
HiPo Manufacturing – Cat III
HiPo Analytical Capabilities
October 2010 - confidential
28
Categorisation
HiPo
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
> 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
(3)
(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
Project Management Communication
Customer
Management
Purchasing
Project Leader
Chemists
CARBOGEN AMCIS
Steering Committee
Ad hoc communication
Weekly Report
Regular Phone Conference
Technical Visits
30
Management
Sales
Project Leader
Chemists
Flexible Approach
Open Business Model
Framework
Agreement
One-off Project
FTE Agreement
Manufacturing
31
Project
• Payment terms
• Forecasting
• Termination
Project
• Resource level
• Payment terms
• Renewal
• Termination
Project
Project
• Payment terms
• Termination
Project
• Project budgets
• Payment terms
• Termination
Project
• Budget ($/Kg)
Project
• FTE Rates
Project
• Overall budget
Project
• Deliverables
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)
 Comprehensive package
 Within available budget &
timelines
 Tailored based on customer
preferences
 40+ Stability Studies
 One-stop-shop to limit the
number of suppliers to be
managed for drug products
and substances
 20+ Chromatography projects
 Commercial track records
 Phase appropriate development
 Lifecycle management
 Robust, reproducible & industryscalable process
 High quality infrastructure
(nonGMP, cGMP)
 Experience from a broad customer
base
 Flawless audit history
 126 standalone analytical projects
 50+ R&D projects
What‘s New ? – Bubendorf, Switzerland
 ~ 4 Mio USD invested
 ~ 1 Mio USD invested
 cGMP clean room for antibody
drug conjugates (ADCs)
 cGMP suite for High Potency
Chromatography
 Sterile room (grade D/ C)
Equipment Available:
 OEL <1 µg/m3 8h-TWA
 3 Walk-in-Barrier Hoods HPLC
10 and 15 cm ID column
 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
 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.
Title
Tel: xx-xxx-xxx-xxx
CARBOGEN AMCIS
Hauptstrasse 171
CH-4416 Bubendorf
Switzerland