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