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 Anti-CD33 antibody conjugated to cytotoxin calicheamicin: withdrawn 2010 but clinical trials ongoing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. $9Bn by 2023, (Roots Analysis)
– 30+ molecules in clinical trials (mid 2013), significant increase in pre-clinical molecules over 2013/2014
mAB
Linker
CytotoxicDrug
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Contents
• Introducing Piramal Grangemouth– Development Groups
– Manufacturing Capabilities
– ADC Commercialisation
– Quality
– Environment, Safety & Health
– Piramal – FujiFim Diosynth Alliance
• Summary
Introducing Grangemouth
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Grangemouth Site History
Primary business is conjugation of Antibody Drug Conjugates
• 2004 First ADC manufactured
• 2005 Business purchased by Piramal
• 2010 US$ 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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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
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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!