Cell and Gene Therapy Challenges associated with supply to larger patients populations: Elements of the CTL019 experience Daniel Stark Head External Supply Cell- and Gene Therapies Development and Manufacturing EBE conference on ATMPs London, December 5 th, 2017
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CTL019 is a living drug designed to target CD19+ B cells Patient s T cell CTL019 cell Anti-CD19 CAR construct CD19 Tumor cell Dead tumor cell Native TCR Lentiviral vector 3 Ex vivo D. Stark, EBE conference on ATMPs, London, 5 th December 2017 Cytokine release CTL019 proliferation In vivo
CTL019 is an autologous immunocellular therapy 1 LEUKAPHERESIS 6 ADMINISTRATION Clinical Site Clinical Site Manufacturing Facility 2 ENRICHMENT & ACTIVATION 4 EXPANSION 3 TRANSDUCTION 5 FORMULATION & QUALITY ASSESSMENT 4 D. Stark, EBE conference on ATMPs, London, 5 th December 2017
Preparation for Commercial Manufacturing Donor Collection Site Moving from one academic facility to many collection sites, multiple manufacturing sites, and many patient treatment sites Manufacturing Administration Site Site Acad emic to Com merci al Donor Collection Sites Shipping Administration Sites Shipping Manufacturing Sites 5 D. Stark, EBE conference on ATMPs, London, 5 th December 2017
Chain of identity (COI) Clinical Site 1 2 3 4 5 Clinical Site 6 Well-established standards for labelling leukapheresis and end-product, use of the Single European Code (Directive 2015/565/EC amending Directive 2006/86/EC on technical requirements for the coding of human tissues and cells) 6 D. Stark, EBE conference on ATMPs, London, 5 th December 2017
Leukapheresis site qualification and collection Clinical Site 1 2 3 4 5 Clinical Site 6 Leukapheresis sites are typically accredited via FACT (US) or JACIE (EU) and in line with local regulations, using or implementing the ISBT-128 labelling standards Novartis performs on-site quality assessments, maintains quality agreements with each site, defines collection and processing requirements, and trains the sites accordingly. The leukapheresis material is cryopreserved prior to shipping Leukapheresis Reference Manual describing minimal requirements to equipment, anticoagulants, procedures, timing, cryopreservation FACT = Foundation for the Accreditation of Cellular Therapy JACIE = Joint Accreditation Committee ISCT-EBMT ISBT=International Society of Blood Transfusion. 7 D. Stark, EBE conference on ATMPs, London, 5 th December 2017
Consistent CTL019 T-cell product from individual patient material Clinical Site 1 2 3 4 5 Clinical Site 6 T cells NK cells Monocytes B cells Incoming leukapheresis material Patient 1 Patient 2 Patient 3 Patient 4 Consistent final product within specifications Patient 1 Patient 2 Patient 3 Patient 4 8 D. Stark, EBE conference on ATMPs, London, 5 th December 2017
Final Product control: release tests Clinical Site 1 2 3 4 5 Clinical Site 6 Identity ü Appearance ü Vector integration Purity ü %T Cells ü Cell viability ü Transduction efficiency Impurities ü Residual beads ü Residual B cells / MRD ü Vector residuals Potency ü Cytokine production ü CAR expression Safety ü Sterility ü Endotoxin ü Mycoplasma ü RCL / vector residuals 9 D. Stark, EBE conference on ATMPs, London, 5 th December 2017
Overall control strategy is based on understanding of CQAs Clinical Site 1 2 3 4 5 Clinical Site 6 Starting Material In Process Controls Materials Controls Control Strategy Final Product Testing Change Control Process Validation CQA: Cri(cal Quality A/ribute CQAs 10 D. Stark, EBE conference on ATMPs, London, 5 th December 2017
Change Control: Managing life cycle of manufacturing Change Driver Process Improvements Automation implementation Etc. Development Summary Report Change Control Initiation Risk Assessment COMPLIANCE RISK Product RA Safety assessment Viral clearance Impurities Process RA Validation CPP/CQA Unit Operations Environment Patient RA Dose Immune response Business RA Sustainability Scalability OVERALL RISK Risk Assessment Report Minor Moderate Major/Uncertain Change Notification to Health Authorities Change Strategy Execute Strategy Study Report Partner Notification Change Implementation Change Control Closure 11 D. Stark, EBE conference on ATMPs, London, 5 th December 2017
Comparability: Use of Split Leukapheresis as starting material Heterogeneity of incoming material T Cells B Cells Monocytes NK Cells Leukapheresis materials Multiple process steps for T cell Isolation Evenly split Process A Process B Harvest Harvest Split healthy donor apheresis (or patient apheresis, if deemed necessary) is used to minimize unrelated variability which might be caused by different starting material in order to better assess the impact of the change. 12 D. Stark, EBE conference on ATMPs, London, 5 th December 2017
Reference manufacturing site model to manage complexity Receive: process changes, analytical changes, specs Gives: process data, trends, investigation, patient response data Technology Transfer Comparability Receive: Process data, trends, investigations, patient response data Future regions or expansion Receive: process changes, analytical changes, specs Gives: process data, trends, investigation, patient response data Gives: process optimization, product enhancements, knowledge Benefit: Preserves consistency of process and product in all regions Risk if not maintained: Process drift over time changes performance and quality of product 13 D. Stark, EBE conference on ATMPs, London, 5th December 2017
Conclusions Manufacturing and supply of autologous products needs to address the following intrinsic challenges: Assurance of Chain of Identity through all supply and manufacturing steps Scale-out of manufacturing and logistics by automation elements Compliant change control management and sound comparability exercises are key tools to perform development and life cycle activities.. Understanding of CQA s is key to successful and efficient development and subsequent commercialization of ATMPs Autologous cell therapies require novel integrated approach to end-toend data management and analysis (from patient starting material to clinical response of patient) to manage development and life cycle of commercial products 14 D. Stark, EBE conference on ATMPs, London, 5 th December 2017
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