Antibody Drug Conjugates

NIBRT 20th June 2014

Jennifer Moore

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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 Anti-CD33 antibody conjugated to cytotoxin calicheamicin: withdrawn 2010 but clinical trials ongoing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

mAB

Linker

CytotoxicDrug

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Contents

• Introducing Piramal Grangemouth– Development Groups

– Manufacturing Capabilities

– ADC Commercialisation

– Quality

– Environment, Safety & Health

– Piramal – FujiFim Diosynth Alliance

• Summary

Introducing Grangemouth

5

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

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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77

Personnel Head Count

• 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)

Manufacturing and Support 43Process Development 12

Analytical Development 9Quality 36

GMP Process Introduction 6Engineering 8

Total 114

Department Personnel

Development Groups

99

Summary of Process Development Experience

• 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

PlatformLab Scale

(> 1g)Toxicology Batch

(25-350g)Total

Auristatins 79 39 118

Maytansines 39 4 43

Duocarmycins 75 0 75

Others 9 1 10

Total 202 44 246

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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

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

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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 areaContainment 10ng/m3 OEL

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Suite 1Suite 2(ADCs)

QC Lab Area(formerly suite 3)

Suite 4(upgrade in progress)

Suite 6(ADCs)

Suite 5(ADCs)

Manufacturing Suites - Overview

(area free for expansion)

Main Offices & Conference Room

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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.

GMP Manufacturing Experience

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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

ADC Commercialisation

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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.

Quality

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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:

Applications in progress for ca. 20 additional countries

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USA Australia Mexico

EU Korea Ukraine

Switzerland Taiwan Japan

Canada Singapore Brazil

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

– -70°C, -20°C, 5°C, 25°C/60%RH (accelerated)

• Outsource sterility and particulates testing

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Analytics for ADC Characterisation

Analytical Category

Typical Assays

Identity•HIC Profile•icIEF Profile

•Dot Blot

Strength •Protein Concentration (UV)

Potency•Drug Load•Binding ELISA

•Cell Based Assay

Purity•SEC Chromatography•SDS-PAGE (Red and Non-Red)•% unconjugated antibody (HIC)

•Conjugate distribution (HIC)•Residual solvent (HPLC)•Residual drug related species (HPLC and LC-MS)

Safety •Bioburden •Endotoxin

Quality•pH•Osmolality

•Excipient levels (Tween)•Appearance (colour and clarity)

ESH at Grangemouth Site

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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

Piramal - FujiFilm Diosynth Alliance

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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

ADC Development Solutions – An Integrated Approach

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• 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

Summary

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ADC Batch History

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Platform Lab Scale

(> 1g)

Toxicology Batch

GMP Phase I/II

GMP Phase III/

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

Thank You!