Julie Kerby, Head of Manufacturing Development Mar 2017 Challenges in developing a flexible, multi-user manufacturing space to accelerate to the clinic Julie Kerby, Head of Manufacturing Development Mar 2017

Why are flexible facilities interesting? 672+ companies worldwide 185 Europe & Israel 112 Asia 349 North America 1 Africa 10 South America 15 Australia & New Zealand Data from Alliance for Regenerative medicine and Informa Sciences SOTI 2015

Why are flexible facilities interesting? Data from Alliance for Regenerative medicine and Informa Sciences SOTI 2015

Why are flexible facilities interesting? Data from Alliance for Regenerative medicine and Informa Sciences SOTI 2015

51 clinical trials in the UK in 2015 The UK landscape 51 clinical trials in the UK in 2015 41 in 2014

UK Cell and gene therapy manufacturing sector 2016 22 facilities >11000m2 total facility footprint 102 cleanrooms >4000m2 total cleanroom footprint 386 full time employees 16 cell therapy manufacturers 6 gene therapy manufacturers 391 full time employees 4 multi-functional (cell and gene) A network of 22 GMP facilities, supplying over 4000m2 of licensed total cleanroom space and a 391  strong workforce with a diverse track record for a range of projects    

Manufacturing facility choice CMO Tech transfer Know-how Scheduling Comparability Owner operated Capitol investment Technical expertise Capacity

Large-scale cell and gene therapy manufacturing centre

Considerations in design Quality Scale Location Flexibility

Quality Risk Management Fundamental to any GMP facility Up to you to demonstrate appropriate control and risk management Codified approach and toolkits Eudralex Volume 4 (framework) etc Complexity elevated in some regards with multi products Question: Controls between batches for single products within the same facility have to demonstrate prevention of cross-contamination. Is it different to preventing cross-contamination with a different batch of autologous product? Risk has to be understood and controlled

Risk Review R i s k C o m u n c a t Risk Assessment Risk Evaluation unacceptable Risk Control Risk Analysis Risk Reduction Risk Identification Review Events Risk Acceptance Initiate Quality Risk Management Process Output / Result of the M g e T l "Quality Risk Management is a systematic process for the assessment, control, communication and review of risks to the quality of the medicinal product across the product lifecycle." ICH Q9 Summarised nicely in ICH guidlines

QRM in reality for CGT multi product centre Future proofed Multi-user Multi-product including Viral vectors QMS & QA interface Client confidentiality EU/US GMP requirements Client expectations Risk Based Approach

QRM in reality Risk based approach Pragmatic Lean Solutions Future proofed Multi-user Multi-product including Viral vectors QMS & QA interface Client confidentiality EU/US GMP requirements Client expectations Risk based approach Lean Solutions Proportionate Physical vs Operational Active Process

Refresh of business model Flexibility for multiple ATMP processes and products Containment for simultaneous ATMP and viral vector manufacture Collaborators will occupy one or more modules Collaborators use their own production staff Collaborators use their own Process and Control documentation EU GMP compliance

External (production) Grade A/B processing environment Risk elements External (production) environment Support areas Cleanroom modules Grade A/B processing environment Personnel QC samples Human starting materials, raw materials and supplies Waste Product

Resulting operational control strategies Complete physical segregation of Grade B / C modules Containment for simultaneous ATMP and viral vector manufacture Simultaneous multiple collaborator occupancy and product manufacture Product segregation QC (IPC) segregation Logistics – incoming and dispatch Know-how and I.P. protection Data segregation Serviced QC space plus segregated space Core QMS with well defined interfaces with collaborator QMS

Design, build and inspection process Use it to better control risk

Stages of build Specification (URS) Build Commission Qualification Building/facilities Equipment Process validation

MHRA inspection stages To discuss strategy, design and operation Planning meetings Planning complete Full set of drawings Pre-building inspection To review progress Discuss changes/deviations During build site visits First formal inspection Facility commissioned Phased inspections Facility and equipment qualification Approval inspection Completion

Outputs of our risk based approach

Flexible module layout 500L STR Allogenic Viral vectors Static systems USP and DSP Min. 6 Autologous processes Tissue products

Flexible module layout 500L STR Allogenic Viral vectors Static systems USP and DSP Min. 6 Autologous processes Tissue products

Flexible module layout 500L STR Allogenic Viral vectors Static systems USP and DSP Min. 6 Autologous processes Tissue products

QA

Controlled quality Manufacturing centre overarching quality systems Inspection and testing QP / QMS Raw materials testing and release Cyro and warehousing Logistics controls Facility License Client quality and manufacturing systems GMP trained operators Manufacturing records Batch release Quality technical agreement

Quality / technical agreement Details technical aspects of the contract between two parties Defines the responsibilities in place between both parties Inspectable by MHRA Will cover QMS Elements (Deviations, complaints, OOS/OOT, product recall, complaints etc.) Material sourcing Roles and Responsibilities Manufacturing modules Shared areas QP agreements

Conclusion

Conclude Quality Risk Management has to be applied to all facilities Assess, understand, manage risk Ongoing-process Reduces chance of failing to manage risk Use physical and operational solutions Physical often better but be pragmatic Regular and open communication with MHRA

Cell and Gene Therapy Catapult 12th Floor Tower Wing Guy’s Hospital Great Maze Pond London SE1 9RT +44 (0)20 3728 9500 info@ct.catapult.org.uk ct.catapult.org.uk Twitter: @CTCatapult Introduction