BioProcess Network 20 th October 2011 CSL s Large Scale Cell Culture Facility Tim Hughes Sr. Dir. Clinical Manufacturing CSL
Objective How to maximise the opportunity to build a state-of-theart facility while minimising risks? Large scale facility scope Facility design needs Facility features Process features Project schedule
New Biotech Facility Drivers CSL in-house current capacity is sufficient for preclinical and early clinical-phase materials, but late-phase supplies are contracted to CMO. Due to the expense and length of clinical trials, there is a strong business case for in-house capability. Business case is strengthened by a strong product portfolio During clinical phases, advantageous to have the ability to respond rapidly to changes in material demands and processes
New Biotech Facility Risks Long build- and delivery timelines often mean that decisions to build are made early Delaying the build decision may delay speed-to-market and increase cost to build Risk of owning a redundant facility due to: Molecules failing to reach late-stage clinical study or market Technology becoming obsolete A redundant facility may have little resaleor reuse value due to geographic location, installations of major equipment and design philosophy
Facility Project Early Specifications Deliver a large scale cell culture facility Footloose location - multiple options Provide required capacity to cater for Phase III clinical trials and early market entry. Accommodate a range of process technologies including recombinant proteins and mabs. Comply with FDA, EU and TGA requirements. Leverage CSL worldwide group technical capabilities
Large Scale Cell Culture Facility Location 6 CSL Broadmeadows site chosen because of the proximity to CSL largescale cell culture expertise at Parkville, large-scale protein purification expertise at Broadmeadows and CSL research capability at Bio21 Institute, Melbourne. Commercial in Confidence
Facility: Key Features Must be able to handle multiple products and technologies at unknown scales and rates Flexibility of use and easy process change-over for campaigns Control highest risks Do not compromise product quality Reduce the risk of a redundant facility Limit capital exposure Delay decision to build as late as possible Control cost of goods Low COGS even at low capacity
Scope Limits Limit of installed scope 200L 500L 2000L Molecule 1 BDI BDS 2000L Limit of design scope 500L 2000L Molecule 2 BDI BDS 2000L Additional capacity for higher capacity and new products will be added when needed. Molecule 3 BDI BDS Ship BDI for processing at CSL Germany
Key Facility Feature: Flexibility Adaptable facility design, allowing incorporation of new technologies for maximum process/ product flexibility.
Decision: Facility Based on Single-Use Systems Benefits: Maximum flexibility in scale, alternative processes and technologies with minimum capital investment Fast change-over; reduced cycle times Risk control Higher assurance; no CIP or SIP required Lower capital investment; simpler/ cheaper build than conventional Facility may be reused for other purposes relatively easily Control cost of goods Decision to build may be delayed Fast build COGS is favourable for process and scales planned
Cost of Goods Cost of Goods with single-use Industry S-U Economic Consensus: Single-use in biotech are cost effective at low titres, low volumes and low utilisation rates Volume/ Titre/ Run rate Various references: BioPharm International, & BioPharm Services Inc.
Single-Use - Risks Higher batch operating expenses Rising cost due to hydrocarbon-source raw material Environmental cost and disposal costs Technology is immature, changing, unstandardised Supply chain concerns Viability of suppliers; single source; quality and reliability is untested Film changes, film variability More manual operations Ergonomics/ handling risks; Operator retraining Process scalability questions Mixing, aeration, flow rates etc. are different to conventional systems Production scale limited at ~2,000L Extractables and leachables questions Validation is more complex Chemical resistance; surface adsorption studies Nevertheless, facilities based on single-use are viable and approvable
Due Diligence for Facility and Process Design Approved Therapeutics: Visited several US companies with FDA approved products in singleuse systems Facility/ Processes: Consulted US thought-leader consultants in facility design and process engineering S-U Suppliers: Visited and audited vendors and their suppliers/ fabricators Process Integrators: Compared capability to provide integration of the entire process stream
Single-use: Challenges / Opportunities Process Adaptation Process must be adapted to volume & flow restrictions, technology limits, surface adsorption, potential gas penetration, higher extractables and leachables, different mixing characteristics & aeration strategies, etc. Validation Increased (& different) process validation Reduced services & utility requirements Reduced start-up & validation; No SIP and CIP QA Features Sterile, 100% containment feature of s-u items influences facility design: Gowning levels Process step segregation Reduced facility air classifications EM monitoring
Facility Design Outcomes Take the opportunity to simplify the conventional facility design model Use ballroom concept for processing areas, separated by process needs Install utility services with 75% turndown capability Use single-use where beneficial, s/s where sensible Use sterile process containers, closures and aseptic connectors on lines 1x 2,000L Upstream train; 1xDownstream train (+ space for more) Use off the shelf, interchangeable & upgradeable components on skids Mobile, modular skids with local controllers for process equipment Uplink skids with standardised, simple interfaces Initially no automated batch functionality or electronic batch records Design facility environment to match opportunities provided by s-u Locate open processing manipulations in HEPA hoods Design and certify at PC2-LS for future use (current cells: Level 1 risk) Increase validation at vendors sites to decrease on-site validation load
Project Schedule Design phases 1 & 2 started July 2009 Commenced construction Nov 2010 Complete mechanical/ process installation July 2012 Complete validation January 2013 Start Eng/GMP February 2013
Elevations FRONT (North) REAR (South) Commercial in Confidence
October 2011 Front view
Level 1 Layout Offices and Utilities FRONT Cold Storage Utilities Offices Commercial in Confidence
Level 2 Layout Process Floor FRONT Circulation Corridor Inoc Media Prep Buffer/Solution Prep Upstream Process Areas (to VI) Downstream Process (BDI) DS Viewing Corridor Commercial in Confidence
Model Process Pre-viral Post-viral
Air Quality- Area Classifications Upstream processing areas - Grade D/ ISO-9 Buffer preparation & BDI to DS processing - Grade C/ ISO-7 Open manipulations: Inoculum preparation (Grade C + Biosafety LAFU) Other open operations in BDI and DS, use sterile connectors
Level 2 HVAC Design Classifications FRONT Commercial in Confidence
Level 2 PC2-LS Certified Area FRONT
Liquid Waste Management GMO+ GMO- -40C freezer
Upstream Train Detail Single-use media prep Single-use inoculum train Shake flasks & Wave bags Single-use bioreactors 200L, 500L, 2000L, operable at 25% Lenticular clarification filters (no centrifuge)
Upstream Concept
Downstream Train Detail Stainless steel and single-use buffer prep S/s Chromatography skids, single-use flow path where feasible 60cm columns with multiple purification cycles for MAbs Single-use 30 cm columns In-line buffer dilution where possible UF/DF single-use flow path
Processing Single-use mixing skids with single-use sterile filtration Sterile bags inside totes for media, buffer and process hold Processing at ambient temperature Low temperature hold / storage: +4 o C, -40 o C & -70 o C
Buffer Prep Concept
Process Services WFI throughout Less cost than a large PW system + small WFI system Process gases Filtered compressed air Heat/cool packs Sterilisation autoclave Continuous heat decontamination unit
GMP Readiness The Operational GMP Readiness and Execution team (OGRE) has the prime objective: Ensure start-up of GMP processing on time OGRE comprises 12 workgroups with unique deliverables Workgroups comprise sub-teams Workgroups collaborate with other groups/ sub-teams
OGRE Stakeholders AdminServices - Security - Access - Reception - Mail/ courier Engineering/ Validation - Protocols - Execution Quality Management - Quality systems admin - Quality implementation - Documentation control - Vendor approvals - Audits - Product changeovers - Batch review - Analytical services - Product release - Process validation Communications - Stakeholder management - Publicity Staff Recruiting/ Training - Staff hiring - Staff orientation - Prescribed training Finance - Business entity - Pricing Engineering Services - Maintenance - Calibration - Primary utilities - Automation - Eng. vigilance OGRE GMP Ops 2013 Information Technology - Communications - BPCS Supply Chain - Material receiving - Released RM storage - Site logistics - Solid waste handling - Hazardous waste - Product shipping HS&E - Oversight - Certification - Specific training Technology Transfer - Analytical services - Specialist training - Technology transfers - Technical oversight - Trouble-shooting - Process qualification - Process validation Regulatory Compliance - Oversight - Agency liaison - Licensing