th
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Anti-CD33 antibody conjugated to cytotoxin calicheamicin: withdrawn 2010 but clinical trials ongoing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 lymphoma and anaplastic large cell lymphomas
• Ado-trastuzumab emtansine (Kadcyla®):
– 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
2 mAB
Linker
Cytotoxic
Drug

Contents
• Introducing Piramal Grangemouth
– Development Groups
– Manufacturing Capabilities
– ADC Commercialisation
– Quality
– Environment, Safety & Health
– Piramal – FujiFim Diosynth Alliance
• Summary

Grangemouth Site History
Primary business is conjugation of Antibody Drug Conjugates
• 2004
• 2005
• 2010
• 2011
• 2012
• 2012
• 2013
• 2013
• 2013
• 2013
• 2014
First ADC manufactured
Business purchased by Piramal
US$ 2M upgrade of facility including Suite 5 for commercial
ADC production
FDA approval for commercial ADCetris supply – first since
Mylotarg (2000)
Strategic alliance with Fujifilm Diosynth Biotechnologies
Site fully licensed by MHRA
GMP ADC Developed & Manufacture >1kg
PMDA (Japan) approval for commercial ADC supply
Additional QC laboratory opened (Lab G)
Corporate approval of US$ 3.5M investment for construction of additional ADC manufacturing suite and WFI plant
ANVISA (Brazil) approval for commercial ADC supply
5

ADC Focus & Talent
D e v e l o p m e n t & M a n u f a c t u r e
Discovery Preclinical Phase 1 Phase 2 Phase 3 Launch Packaging
Marketing,
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

Personnel Head Count
Department
Manufacturing and Support
Process Development
Analytical Development
Quality
GMP Process Introduction
Engineering
Total
Personnel
43
12
9
36
6
8
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)

Summary of Process Development Experience
Platform
Auristatins
Maytansines
Duocarmycins
Others
Total
Lab Scale
(> 1g)
79
39
75
9
202
Toxicology Batch
(25-350g)
39
4
0
1
44
Total
118
43
75
10
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

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

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, inprocess, 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
11

ADC Manufacturing - Facility
• One Commercial ADC GMP Manufacturing Suite (Suite 5, 372m 2 )
• Two Clinical GMP ADC Manufacturing Suites (Suites 2 [137m 2 ] & 6
[270m 2 ])
• A fourth suite dedicated to manufacture of antibody conjugates is under construction [420m 2 ] (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/m 3 OEL

Manufacturing Suites - Overview
Suite 1
Suite 2
(ADCs )
QC Lab Area
(formerly suite 3)
(area free for expansion)
Main Offices & Conference Room
Suite 4
(upgrade in progress)
Suite 6
(ADCs)
Suite 5
(ADCs)

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 7m 2 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.

GMP Manufacturing Experience
Platform
Auristatins
Maytansines
Duocarmycins
Total
GMP Phase I/II
140
13
25
178
GMP Phase III/
Commercial
88
7
0
95
Highlights
• Manufactured over 270 GMP batches
• Current projects at >1kg scale
• 22 different products manufactured to GMP
16

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

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

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

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

Commercial ADC Supply
Global commercial supply established into the following markets:
USA
EU
Switzerland
Canada
Australia
Korea
Taiwan
Singapore
Mexico
Ukraine
Japan
Brazil
Applications in progress for ca. 20 additional countries

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

Quality Control
• Two laboratories dedicated to QC (400m 2 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
– -70°C, -20°C, 5°C, 25°C/60%RH (accelerated)
• Outsource sterility and particulates testing

Analytics for ADC Characterisation
Analytical
Category
Identity
•HIC Profile
•icIEF Profile
Typical Assays
•Dot Blot
Strength
Potency
Purity
•Protein Concentration (UV)
•Drug Load
•Binding ELISA
•SEC Chromatography
•SDS-PAGE (Red and Non-Red)
•% unconjugated antibody (HIC)
Safety
Quality
•Bioburden
•pH
•Osmolality
•Cell Based Assay
•Conjugate distribution (HIC)
•Residual solvent (HPLC)
•Residual drug related species (HPLC and LC-MS)
•Endotoxin
•Excipient levels (Tween)
•Appearance (colour and clarity)

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

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

Alliance Benefits - Overview
– 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

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

ADC Development Solutions – An Integrated
Approach
– 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
33

ADC Batch History
Platform
Auristatins
Maytansines
Duocarmycins
Lab Scale
(> 1g)
79
39
75
Others
Total
9
202
Toxicology
Batch
39
GMP Phase
I/II
140
GMP Phase III/
Commercial
88
4
0
13
25
7
0
1
44
0
178
0
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

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