Establishing a Facility for GMP Manufacture of High...
Transcript of Establishing a Facility for GMP Manufacture of High...
Your Biologics and Vaccines CDMO Partner of Choice.
Establishing a Facility for GMP Manufacture of High Potency Biologics
Nigel Shipston Ph.D., Head of Programme Design June 22, 2016
One Global Company
3 SITES
Billingham, UK College Station, TX RTP, North Carolina
1,100 EMPLOYEES
World Wide
6 LICENSES
For commercial manufacturing.
35+ YEARS
Of Biologics CDMO experience.
300+ MOLECULES
In process development and/or manufacturing.
Regulatory
Approval Launch Phase III Phase I Phase II Preclinical
With you all along the road To clinical success
Gene Expression &
Strain / Cell Line Development
Process Invention
Pre-clinical
Manufacture
Process Development & Optimization
Analytical & Stability
cGMP Manufacture
Fill/Finish
Process Characterization
Process Validation
cGMP
Manufacture
Stability
Commercial Production
Post-approval
Activities
High Potency Biologics
Transgenic Expression
Orally dosed proteins
Precision Medicines
60+ mAb, mAb-like
and Ig-fusion
molecules
175+ non-mAb
recombinant proteins
30+ Vaccine programs
Full development / GMP manufacturing
Breadth and Depth in our experience
• High Potency Biologics - an increasingly important class of therapeutics
• Cytotoxic proteins - Apoptosis signals (TNFα and variants)
- Some cytokines (Interleukins)
• Significant business opportunity
• Significant challenge to establish a multi-product facility - Facility design
- Operating strategy
High Potency Biologics Manufacturing
Opportunity and Challenges
Banding Scheme at Fujifilm Diosynth*
ADE Category
ADE Range Approach Examples
Band A
<1ng/day
Not manufactured in FDB multi-product facility
Lethal toxins e.g. botulinum toxin, diptheria toxin
Band B
1ng-100ng/day
Risk assessment -additional controls necessary
Toxins, apoptosis signals , some cytokines e.g. TNFα, Interleukins
Band C
100ng-10ug/day
Risk assessment –some additional controls likely
Cytokines, growth factors e.g. interferons, human growth hormone
Band D
>10ug/day
Existing controls appropriate
Monoclonal antibodies, antibody fragments, scaffold proteins, enzymes, insulin
* Card J.W. et al., Regulatory Toxicology and Pharmacology 73 (2015) 595-606
• Establish a GMP Facility for manufacturing (microbial derived) High Potency Biologics
• GMP production from vial thaw to drug substance bulk fill
• Multi-product capability/versatility was critical
• Suitable for manufacture of early/late phase clinical and commercial products
High Potency Biologics Manufacturing Facility
Project Goals
• Re-purpose and upgrade an existing microbial GMP facility to provide self-contained cleanrooms with separate HVAC system(s)
• Design facility in consultation with the UK regulatory agency (MHRA) to expedite regulatory approval
• Completion of expertly detailed Failure Mode Effects Analysis (FMEA) assessment on existing procedures. Outputs of FMEA embedded in facility design, equipment URS’, procedures and training
High Potency Biologics Manufacturing Facility
Project Strategy
Design and Construction Timelines
Design Phase March 2014-
July 2014
Consultation MHRA
August 2014
Construction Begins
July 2015
Construction Ends
February 2016
Commissioning Qualification Complete
April 2016
First GMP Batch Begins
April 2016
Seven (7) Months
Three (3) Months
Two Years from concept to fully operational
High Potency Facility Floorplan
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Total floor area: ~3000 sqft Upstream processing: ~1000 sqft Downstream processing: ~1250 sqft
USP DSP Inoc
Suite Layout: USP
Suite Layout: USP/DSP Transfer Port
Suite Layout: DSP
Operations
Guiding Principles
FACILITY OPERATING STRATEGY
PROCESS CONTAINMENT
STRATEGY
HIGH POTENCY BIOLOGICS GMP
PRODUCTION
• Segregated “once through” HVAC system with HEPA extraction
• Dedicated personnel and material access routes
• Dedicated direct product contact equipment
• Non-product contact equipment with disposable flow-path remains multi-product use where risk assessment allows:
‒ Surface Removal and Product Degradation Methods Established
‒ Execution Of Qualified Surface Cleaning Protocols
Operating Principles
FACILITY OPERATING STRATEGY
• Personnel
‒ Single Use Disposable Gowning
‒ Control Of Personnel Movement Between Facilities
• Engineering solutions eliminate all risk of contamination to utilities
• Closed processing unit ops…as far as possible - minimizing exposure of operators and facility to product
• If closed processing operations are not achievable for certain unit ops they are operated within a secondary containment envelope
Personnel and Process Controls
FACILITY OPERATING STRATEGY
Risk assessments (FMEA) performed to ensure appropriate mitigation to minimize loss of process containment
Additional risk mitigation:
• Closed sampling and analysis
• Testing of connections and joints, prior to use
• Use of single use disposable consumables including columns
• Deactivation / flushing of product flow-path prior to breaking of connections
• Tube welding used for process connections
• Use of tube sealing at point of disconnection
• Aerosol generation studies for higher risk areas
• All process waste collected for off-site disposal
• Segregated vent lines
Process Containment
PROCESS CONTAINMENT
STRATEGY
• Enhanced procedures followed in the event of a leak, drip or spill
• Rapid response to loss of containment events following procedure specified above
• Procedure to utilize clean-up agent and contact time that has been demonstrated to achieve effective product removal and degradation
• Frequent in-glove changing following high risk activities
• Sample transport mechanism to provide secondary containment
• Spill equipment / materials availability utilizing low aerosol generation clean-up technology
• Waste containment and disposal
Enhanced Control Procedures: Loss of containment
• Establishment of facility from concept to commissioning took 2 years
• Operational and Procedural control strategies are in place
• Facility is up and running - Late Phase Clinical Manufacturing project underway
• GMP Facility is now available for High Potency Biologics Production (‘clinical and commercial ready’)
Conclusions
Your Biologics and Vaccines CDMO Partner of Choice.
Your Biologics and Vaccines
CDMO Partner of Choice