Antibody Drug Conjugates

NIBRT 20th June 2014

Jennifer Moore
The ADC Opportunity

Targeted therapy, proven effectiveness

Antibody (or fragment) linked via stable chemical
linker to biologically active cytotoxic (anti-cancer)
Gemtuzumab ozogamicin (Mylotarg): Approved 2000.
Anti-CD33 antibody conjugated to cytotoxin
calicheamicin: withdrawn 2010 but clinical trials ongoing
Brentuximab vedotin (Adcetris):
anti-CD30 antibody conjugated via cleavable linker to
cytotoxic monoethyl auristatin (MMAE) Hodgkins Linker
lymphoma and anaplastic large cell lymphomas
Cytotoxic
Ado-trastuzumab emtansine (Kadcyla):
mAB Drug
anti-Her2 antibody conjugated via non-cleavable linker to
cytotoxic DM-1 (derivative of maytansine) Her2
metastatic breast cancer
Market predicted to grow significantly
E.g. $9Bn by 2023, (Roots Analysis)
30+ molecules in clinical trials (mid 2013), significant
increase in pre-clinical molecules over 2013/2014

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Contents

Introducing Piramal Grangemouth

Development Groups
Manufacturing Capabilities
ADC Commercialisation
Quality
Environment, Safety & Health
Piramal FujiFim Diosynth Alliance
Summary

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Introducing Grangemouth
Grangemouth Site History

Primary business is conjugation of Antibody Drug Conjugates

2004 First ADC manufactured

2005 Business purchased by Piramal
2010 US$ 2M upgrade of facility including Suite 5 for commercial
ADC production
2011 FDA approval for commercial ADCetris supply first since
Mylotarg (2000)
2012 Strategic alliance with Fujifilm Diosynth Biotechnologies
2012 Site fully licensed by MHRA
2013 GMP ADC Developed & Manufacture >1kg
2013 PMDA (Japan) approval for commercial ADC supply
2013 Additional QC laboratory opened (Lab G)
2013 Corporate approval of US$ 3.5M investment for construction
of additional ADC manufacturing suite and WFI plant
2014 ANVISA (Brazil) approval for commercial ADC supply

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ADC Focus & Talent

Development & Manufacture

Marketing,
Discovery Preclinical Phase 1 Phase 2 Phase 3 Launch Packaging Sales &
Distribution

Core Services
Lab scale & toxicology supply
Early phase clinical supply
Late phase clinical supply
Launch & commercial supply

Core Competencies
Process development
Process optimization & robustness
Analytical, bioanalytical & stability
Technology transfer & scale-up

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Personnel Head Count

Department Personnel

Manufacturing and Support 43

Process Development 12
Analytical Development 9
Quality 36
GMP Process Introduction 6
Engineering 8
Total 114

Head count currently 114 personnel

70% qualified to degree level or above
Head count predicted to increase to 120 by end 2014
Approximately 30% of personnel dedicated to GMP Quality
activities (QC, QA, QMS)

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Development Groups
Summary of Process Development Experience

Lab Scale Toxicology Batch

Platform Total
(> 1g) (25-350g)

Auristatins 79 39 118

Maytansines 39 4 43

Duocarmycins 75 0 75

Others 9 1 10

Total 202 44 246

Experience in a broad range of protein conjugations

Small molecule toxin conjugates (34 different toxins / toxin linkers)
Traditional and site specific conjugation
Other conjugates such as protein conjugates, chelators for radioimmunotherapy,
PEGylation
IgG2 and IgG4 (difficult to conjugate mAbs) and low purity mAbs
Drug linkers which are difficult to clear
All standard ADC processing techniques including aggregate removal
116 distinct ADC candidates made at Piramal
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Services Offered Through Process Development
Group

Process development activities

Development and optimisation of supporting purification techniques (TFF
and chromatography)
Supporting analytics developed (in-process tests and final product)
Robustness and process characterisation studies
Basic formulation studies
Conjugation chemistry optimisation
Experience of statistical experimental design

Support introduction and ongoing GMP manufacture

Supported Auristatin project from initial toxicology batches to commercial
launch
Scale up to >1kg for Auristatin processes
Support ongoing commercialisation activities

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Analytical Development Group

Highly experienced group of staff with extensive industry experience

performing:

Support of Process Development Analytics

Method Development for: HPLC (HIC, SEC, PLRP, RPC), icIEF, SDS-
PAGE, ELISA, Cell Based Assays and cleaning methods
Qualification / Validation or Transfer of Methods raw material, in-
process, release testing and cleaning methods
All non-development activities performed to GMP using QC trained
staff and qualified instrumentation
Act as SMEs, supporting routine QC activities
Support of Proof of Concept studies development and conduct of
cell based assays in targeted cell lines
Support commercialisation activities, e.g. product characterisation

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ADC Manufacturing
ADC Manufacturing - Facility

One Commercial ADC GMP Manufacturing Suite (Suite 5, 372m2 )

Two Clinical GMP ADC Manufacturing Suites (Suites 2 [137m2] & 6
[270m2])
A fourth suite dedicated to manufacture of antibody conjugates is under
construction [420m2] (expected on-line Dec 2014).
Multi-product manufacturing facility, manufacturing performed on a
campaign basis.
Facility containment
- Glove box isolator
- Vented cupboards
- Biosafety cabinet
Standards
EU GMP Grade C (Class 10,000) processing area
EU GMP Grade B (Class 100) finishing area
Containment 10ng/m3 OEL

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Manufacturing Suites - Overview

Suite 2 QC Lab Area Suite 4

Suite 1
(ADCs) (formerly suite 3) (upgrade in progress)

Suite 6
(area free for expansion) (ADCs)

Suite 5
Main Offices & Conference Room (ADCs)

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Equipment & Cleaning Philosophy

Use of stainless steel, glass and disposable equipment

Batch sizes up to 2kg (input mAb)
Up to 750L reactive volume capability depending on complexity
Philosophy of dedicated or single use product-contact manufacturing
components
Stainless steel and glass reaction vessels
Stainless steel TFF systems up to 7m2 area
Disposable transfer lines and filling manifolds
Mixing bag systems
Cleaning
We dedicate equipment to clients and toxin
Cleaning limits are based on an ADE calculation based on principle from
the ISPE Risk-MaPP guidelines
Cleaning has been reviewed by MHRA, FDA, PMDA and ANVISA and
deemed acceptable.

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GMP Manufacturing Experience

Platform GMP Phase I/II GMP Phase III/

Commercial
Auristatins 140 88

Maytansines 13 7

Duocarmycins 25 0

Total 178 95

Highlights
Manufactured over 270 GMP batches
Current projects at >1kg scale
22 different products manufactured to GMP

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ADC Commercialisation
ADC Commercialisation

Process Characterisation
Identify product quality attributes
Categorise process parameters
Risk assessment/process mapping
Perform characterisation studies
Process Justification Reporting

Raw Material Qualification / Vendor Assurance

Analytical Method Validation
Equipment Qualification

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ADC Commercialisation

Process Validation
Process conformance studies, impurity clearance, mixing
study (formulation step), drug substance homogeneity,
freeze down studies.
Cleaning Validation
Inter batch cleaning, clean / dirty hold times, process /
cleaning agent residue removal, microbial quality,
(depyrogenation / sanitisation steps), resin / membrane
cleaning.

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Quality
Regulatory History

FDA Audits
FDA Pre-Approval Inspection 2011 FDA approval granted for commercial
supply
FDA June 2013 routine inspection, 4 items all closed

MHRA Audits
Successful MHRA audits in 2004, 2006, 2009 & 2012
Most recent audit June 2014 no critical or major observations
Site fully licensed by MHRA

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Regulatory History

PMDA (Japan) Pre-Approval Inspection September 2013

No critical or major observations
Approval granted for commercial supply of ADC BDS

ANVISA (Brazil) Pre-Approval Inspection September 2013

No critical or major observations
Approval granted for commercial supply of ADC BDS

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Commercial ADC Supply

Global commercial supply established into the following

markets:

USA Australia Mexico

EU Korea Ukraine

Switzerland Taiwan Japan

Canada Singapore Brazil

Applications in progress for ca. 20 additional countries

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Quality Management Systems and ADC Quality

Quality Management System in line with EU, FDA & ICH guidelines
QMS is currently aligned with Part II EU GMP/Q7
Site has a full GMP licence for commercial and clinical drug product and API
Clinical and Commercial ADCs are released by QP

Quality Assurance, Qualification and Validation team

Site Quality team has 100+ years of GMP experience
Site QA team has 20+ years of experience with ADC manufacture and testing
5 of the current team have experience in commercialisation, including hosting Pre-
Approval Inspections for ADCs for FDA, MHRA, PMDA and ANVISA

Corporate Quality Governance

Site Head of Quality reports to Piramal Corporate Quality General Manager
Site reports monthly QMS metrics offsite to Corporate Quality
Site has monthly QMRT meeting including Site Lead and Head of Operations

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Quality Control
Two laboratories dedicated to QC (400m2 area)
10 year history of routine testing of ADCs including cell based assays and
ELISA
Strong experience with ADC method transfer, development and validation
studies
QC personnel are aligned with clients to provide continuity through the
lifecycle of a project
34 personnel in total, including 9 in development
Testing to support routine GMP operations are performed in-house
Toxicology, BDS and FDP release testing
Stability studies to ICH Q1:
History of 80 studies performed/in progress
Tox, DS, DP and reference materials
-70C, -20C, 5C, 25C/60%RH (accelerated)
Outsource sterility and particulates testing

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Analytics for ADC Characterisation

Analytical
Typical Assays
Category
HIC Profile Dot Blot
Identity
icIEF Profile

Strength Protein Concentration (UV)

Drug Load Cell Based Assay

Potency
Binding ELISA
Conjugate distribution (HIC)
SEC Chromatography
Residual solvent (HPLC)
Purity SDS-PAGE (Red and Non-Red)
Residual drug related species (HPLC
% unconjugated antibody (HIC)
and LC-MS)

Safety Bioburden Endotoxin

pH Excipient levels (Tween)

Quality
Osmolality Appearance (colour and clarity)

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ESH at Grangemouth Site
Health and Safety

Site dedicated ESH Manager supported by wider Piramal ESH plus site based Employee
Safety Representatives

Operate in compliance with the Health and Safety at Work Act and other UK
Regulations

Site Enforcing Authority is the Health and Safety Executive (HSE) no Improvement
notices or enforcement notices

All projects are assessed under Control of Substances Hazardous to Health Regulations
(COSHH)

We operate our own in-house 5-band system for potent materials

On site Occupational Health Department and Health Surveillance

On site Emergency Services - 24/7 cover (Top Tier COMAH site)

Experience:
- Potent prostaglandin for >20 years

- Cytotoxics for ~15 years

- ADCs for >10 years

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Environmental

Annual audits from Scottish Environmental Protection Agency

(SEPA)
Manufacturing and warehousing operate under IPPC permit Part A
Retained excellent rating for 2013
Waste management all streams managed through licensed waste
contractors
Manufacturing buildings have contained drainage which can be
isolated from site waste streams
Site has on site effluent treatment plant (ETP) with divert capability
to prevent spills leaving site
Dedicated bunded hazardous waste area spills would be contained
Quarterly IPPC meetings with all Companies on site including ETP

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Piramal - FujiFilm Diosynth Alliance
 Alliance Benefits - Overview

Piramal - Fujifilm Diosynth:

Integrated Antibody + ADC process

development and GMP manufacturing
Flexible programmes
mAb cell line development
mAb and ADC process optimisation
Small scale and toxicology supply of mAb
and ADC
GMP: Phase I/II/III, Process
Characterisation, Process Validation, Launch
and Commercial supply

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Alliance Benefits: ADC Development Challenges

Antibody
Selection of lead antibody candidate
Site specific conjugation technologies

Conjugation
Site of conjugation and impact on stability and
pharmacokinetics
Extent of and control of heterogeniety
DAR optimisation and characterisation
Optimisation and control of reaction steps
ADC analytics

Formulation
Antibody generally good track record of stability
BUT: Many small molecule drugs relatively hydrophobic:
potential for hydrophobicity driven aggregation

Cost of goods
FujiFilm Diosynth Piramal alliance offers an
integrated approach to common challenges
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ADC Development Solutions An Integrated
Approach

Piramal - Fujifilm Diosynth Offers:

Extensive biologics and drug chemistry
expertise
Integrated development programmes:
Flexibility
Delivery of material for PoC studies
Speed
Manufacturing challenges understood
Exploit pre-optimised generic platforms
mAb, ADC, Analytics
Robust process design approach
Gene>Clinical>Commercial Offer
underpinned by
Regulatory inspection track record

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Summary
ADC Batch History

Platform Lab Scale Toxicology GMP Phase GMP Phase III/

(> 1g) Batch I/II Commercial
Auristatins 79 39 140 88

Maytansines 39 4 13 7

Duocarmycins 75 0 25 0

Others 9 1 0 0

Total 202 44 178 95

Highlights
Manufactured over 500 batches (>270 GMP)
Experience with over 100 distinct ADC
candidates
Current GMP projects at >1kg scale
22 different products manufactured to GMP

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Summary

Piramal is the world leader in ADC process development, GMP

manufacture & scale-up.
Broad experience and expertise with various conjugation platforms.
CMO industry leader with regards number and variety of GMP ADC
clinical and commercial batches successfully manufactured
Client focused, flexible and work collaboratively with our customers.
Strong regulatory history which is constantly expanding in line with
worldwide roll out of commercial ADC.
Continue to invest in the facility to meet the demands of our clients
and the market (recent investments of $3.5 million made in site
upgrades, management infrastructure and scientific capabilities)
Continue to investigate alliances to provide integrated solutions for
our clients

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Thank You!