Transcript Antibody Drug Conjugates
Antibody Drug Conjugates NIBRT 20
th
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 Anti-CD33 antibody conjugated to cytotoxin calicheamicin: withdrawn 2010 but clinical trials ongoing • Brentuximab vedotin (Adcetris®): – anti-CD30 antibody conjugated via cleavable linker to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
• 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. $9Bn by 2023, (Roots Analysis) – 30+ molecules in clinical trials (mid 2013), significant
increase in pre-clinical molecules over 2013/2014
2 mAB Linker Cytotoxic Drug
Contents
• Introducing Piramal Grangemouth – Development Groups – Manufacturing Capabilities – ADC Commercialisation – Quality – Environment, Safety & Health – Piramal – FujiFim Diosynth Alliance • Summary
Introducing Grangemouth
Grangemouth Site History Primary business is conjugation of Antibody Drug Conjugates
• 2004 • 2005 • 2010 • 2011 • 2012 • 2012 • 2013 • 2013 • 2013 • 2013 • 2014 First ADC manufactured Business purchased by Piramal US$ 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)
Development Groups
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, 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 11
ADC Manufacturing
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
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
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
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 Safety Quality
•Protein Concentration (UV) •Drug Load •Binding ELISA •SEC Chromatography •SDS-PAGE (Red and Non-Red) •% unconjugated antibody (HIC) •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)
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
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
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
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
• 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 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