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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calicheamicin: withdrawn 2010 but clinical trials ongoing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
lymphoma and anaplastic large cell lymphomas
Linker
• 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. $9Bn by 2023, (Roots Analysis)
– 30+ molecules in clinical trials (mid 2013), significant
increase in pre-clinical molecules over 2013/2014
2
mAB
Cytotoxic
Drug
Contents
• Introducing Piramal Grangemouth
– Development Groups
– Manufacturing Capabilities
– ADC Commercialisation
– Quality
– Environment, Safety & Health
– Piramal – FujiFim Diosynth Alliance
• Summary
3
Introducing Grangemouth
Grangemouth Site History
Primary business is conjugation of Antibody Drug Conjugates
• 2004
First ADC manufactured
• 2005
Business purchased by Piramal
• 2010
US$ 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
5
ADC Focus & Talent
Development & Manufacture
Discovery
Preclinical
Phase 1
Phase 2
Phase 3
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
6
Launch
Packaging
Marketing,
Sales &
Distribution
Personnel Head Count
Department
Personnel
Manufacturing and Support
Process Development
Analytical Development
Quality
GMP Process Introduction
Engineering
43
12
9
36
6
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)
7
Development Groups
Summary of Process Development Experience
Platform
Lab 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
• 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
9
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
10
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, SDSPAGE, 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
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
13
Manufacturing Suites - Overview
Suite 1
Suite 2
(ADCs)
QC Lab Area
(formerly suite 3)
Suite 4
(upgrade in progress)
Suite 6
(ADCs)
(area free for expansion)
Suite 5
(ADCs)
Main Offices & Conference Room
14
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.
15
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
16
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
18
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.
19
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
21
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
22
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
23
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 PreApproval 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
24
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
25
Analytics for ADC Characterisation
Analytical
Category
Identity
Typical Assays
•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)
26
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
28
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
29
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
31
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
32
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
33
Summary
ADC Batch History
Platform
Lab Scale
GMP Phase
I/II
GMP Phase III/
(> 1g)
Toxicology
Batch
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
35
Commercial
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
36
Thank You!