adapting tech transfer to non-platform...
TRANSCRIPT
Adapting Tech Transfer to non-Platform
ProcessesCase Study
JOHN COYNE SR MANAGER ANDOVER PILOT PLANT
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Case Study
JOHN COYNE SR MANAGER ANDOVER PILOT PLANT
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Adapting Tech Transfer to Atypical Processes
Case Study
JOHN COYNE SR MANAGER ANDOVER PILOT PLANT
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Adapting Tech Transfer to Complex Processes
Pfizer BioTherapeutics
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Bioprocess R&D Pfizer Global Supply
Tech Transfer
Pfizer BioTherapeutics
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Bioprocess R&D Pfizer Global Supply
Tech Transfer
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Pfizer BioTherapeutics Locations
Grange Castle, Ireland Sandford, NC
St. Louis, MO
Durham, NC
Pearl River, NYAndover, MA
Andover, MA
BRD
PGS
Stragnas, Sweden Hangzhou, China
BRD Deliverables• Early Discovery Support – enable candidate selection
• Development, characterization and Tech Transfer of Cell Lines for Protein Production; MCB/WCB generation, storage and stability programs
• Process Development and process understanding from IND Registration Toxicology (“Reg Tox”) through Commercial
• Support in-licensing
• Technology transfer to non-clinical and clinical manufacturing plants and commercial manufacturing sites – internal and CMOs
• Manufacture of drug substance for non-clinical and clinical trial material (CTM)
• Strategy, content and authoring of regulatory submissions and responses to regulatory questions
• Support of manufacturing through to validation
• Membership on PSPT and Co-Dev teams
• Novel technology development
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BRD Pilot Plant & Clinical Manufacturing
Operations
• Manufacture Regulatory Toxicology Supplies
• Manufacture Phase 1 & 2 Clinical Supplies
• Perform process development and scale up experiments
• Maintain Regulatory Compliance
Pilot Plant Facilities:
Non-GMP• Andover (APF): 1x 100 L, 2 x 150 L, 1x200L SUB, 1x 1000L SUB and 2X500 L (mammalian cell culture)
• St. Louis: 4 x 30 L, 3 x 100 L, 1 x 250 L (mammalian cell culture)
1 x 100 L, 1 x 1200 L (microbial fermentation)
GMP Clinical Manufacturing St. Louis:• Suite One:1 x 500 L 1 x 1000 L and 1 x purification suite (mammalian cell culture)
• Suite Two:1 x 100 L, 1 x 500 L, 2 x 2500 L and 2 x purification suites (dual-use, microbial and mammalian)
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BRD Pilot Plant & Clinical Manufacturing
Operations
• Manufacture Regulatory Toxicology Supplies
• Manufacture Phase 1 & 2 Clinical Supplies
• Perform process development and scale up experiments
• Maintain Regulatory Compliance
Pilot Plant Facilities:
Non-GMP• Andover (APF): 1x 100 L, 2 x 150 L, 1x200L SUB, 1x 1000L SUB and 2X500 L (mammalian cell culture)
• St. Louis: 4 x 30 L, 3 x 100 L, 1 x 250 L (mammalian cell culture)
1 x 100 L, 1 x 1200 L (microbial fermentation)
GMP Clinical Manufacturing St. Louis:• Suite One:1 x 500 L 1 x 1000 L and 1 x purification suite (mammalian cell culture)
• Suite Two:1 x 100 L, 1 x 500 L, 2 x 2500 L and 2 x purification suites (dual-use, microbial and mammalian)
Coming in 2019
Andover GMP Clinical Manufacturing Facility
• 5 Manufacturing Suites
• 2 x 1000L SUB
• 1 x 2000L SUB
• 1 x 1200L SS dual-use, microbial and mammalian
Andover Pilot Plant: What We Do
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ANDOVER PILOT
FACILITY (APF)
CELL CULTURE PROCESS
DEVELOPMENT (CPD)
PURIFICATION PROCESS
DEVELOPMENT (PPD)
Clinical Supply
(PGS, Pharm Sci, CMO)
CELL LINE
DEVELOPMENT (CLD)
The Andover Pilot Facility
(APF) is a team of dedicated,
talented engineers, scientists
and technicians that support
the Bioprocess Research &
Development Manufacturing
Group
Reg ToxSupply
Team Supply 2 Material
Tech Dev.
Late Stage Process Support
Next Generation
Process Support
Pfizer’s World Class Biotherapeutics Manufacturing
Embraces Both Capabilities and CapacitiesO
ve
rall
Ca
pa
bili
tie
s • More than 7,000 colleagues worldwide
• Nine manufacturing sites
• CMO management expertise: >15 CMOs
• Supports over $12B in sales revenue for 90+ markets
• Product portfolio of 14 products and over 3000 SKUs
• Strong global scientific and business expertise
• World class technology platformD
rug
Su
bsta
nce
• Mammalian:
• Grange Castle, Ireland
• Andover, MA, USA
• Boehringer-Ingelheim
Biberach, Germany
• CMOs
• Microbial:
• Sanford, USA
• Strangnas, Sweden
• Pearl River, USA
• Gene Therapy:
• Sanford, USA
Dru
g P
rod
uct a
nd
Pa
cka
gin
g • Grange Castle, Ireland: Syringes
• Algete, Spain: Vials
• Dublin, Ireland: Vials
• Pearl River, USA: Vials and Syringes
• Puurs, Belgium: Syringes
• Havant, UK: Vials, Packaging and Distribution
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Pfizer’s Diverse Pipeline:
Delivering on Multiple Molecular Modalities
• Antibodies
– Standard Mab platform process using Protein A affinity capture (ProA), anion exchange chromatography
(AEX) polishing step, virus filtration (VRF) and ultrafiltration/diafiltration (UF/DF) for formulation
• Antibody Drug Conjugate (ADC)
– Typically standard mAb platform process but additional work may be required because of conjugation of
molecule
• Fc-Fusions
– Protein A Affinity capture step, VRF and UF/DF; may require non-platform chromatography steps (i.e.
cation exchange (CEX) , hydrophobic interaction (HIC) or ceramic hydroxyapatite (CHA) to address
increased aggregation, clipping or stability issues
• Therapeutic Proteins (e.g. Clotting Factors, recAP, Lagova, enzymes)
– Complicated processes employing multiple chromatography steps, precipitation, refolding, etc. and
analytics requiring more extensive development
• Vaccines (e.g. Trumenba, Prevnar, Staph A, C. diff, GBS, PNG)
– Extremely diverse modalities (microbial proteins, polysaccharides, VLPs)
– A number of molecules /processes make up one vaccine product (multivalent)
– Typically non-platform processes with unique challenges
• Gene Therapy (e.g. Duchennes Muscular Dystrophy, Factor IX, Factor VIII, Friedrich’s Ataxia)
– Early and late stage viral vector product pipeline with varying vector serotypes
– A platform process is being developed that can be used for future products
Pfizer Confidential │ 12Slide courtesy of Mary Switzer
Research Ph IIa Ph IIb Ph III File BLALead
Dev.Ph I
Pre
ClinicalCommercial
PhRD
QA
CMC
ARD
BRD
SCC
PM
OS
PSTL
PoC
PhRD
QO
CMC
ARD
BRD
SCC
PM
OS
Co-Dev
Lead
GMS
Bus. OpsLaunch
Co-Dev
Team
PSPT
Comparison of Early and Late Stage Teams
Slide courtesy of Mary Switzer
Research Ph IIa Ph IIb Ph III File BLALead
Dev.Ph I
Pre
ClinicalCommercial
PhRD
QA
CMC
ARD
BRD
SCC
PM
OS
PSTL
PoC
PhRD
QO
CMC
ARD
BRD
SCC
PM
OS
Co-Dev
Lead
GMS
Bus. OpsLaunch
Co-Dev
Team
PSPT
Comparison of Early and Late Stage Teams
Analytical
Sub-TeamARD
Drug Substance
Sub-TeamBRD
Andover
Technology Transfer Team
Slide courtesy of Mary Switzer
Delivering Medicine to Patients
Most Trusted
Efficiency
Quality
SpeedCost
Speed: Asset/BTxPS/PGS
• Based on competitive landscape – 1st, 2nd, 3rd to market?
• Speed to go/no go decision
• Clinical need for acceleration – i.e. breakthrough therapy
• Project prioritization/Facility availability
Quality: BTxPS/PGS
• Define a DS Mfg Process that delivers consistent drug
substance supply
Cost: Asset/BTxPS/PGS
• Appropriate investment cost ($) and resources
to deliver project
• Cost of Goods (COGs) targets for commercially
viable process
Slide courtesy of Mary Switzer
Basis Of Design With The End In Mind
Commercial Drug Substance Process
Control of Post Translational Modifications
(PTMs)
Control of Process Related
Impurities
Control Product Related
ImpuritiesCost of Goods
Process Robustness Facility FitRegulatory
Expectations
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Establish robust and economical processes delivering safe products to patients
CHALLENGES
Slide courtesy of Mary Switzer
Process Development Balancing Act
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Cost Quality
Slide courtesy of Mary Switzer
Challenges in Late Stage Development
• Unique for each program
• Maintain comparability as Process Evolves during Development
• Heightened Characterization
• Accelerated timelines (unmet clinical need)
• Portfolio Diversity (in-house & in-licensed assets, more than mAbs)
18Slide courtesy of Mary Switzer
Tech Transfer Timeline
Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec
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Tech Transfer (Pilot)
Pilot
Campaign
Tech Transfer (Clinical)
Clinical
Campaign
Typical Process Timeline
• PSPT or CoDEV teams established
• Tech Transfer to Pilot for reg tox campaign
• Tech Transfer to clinical manufacturing site (minimal Pilot Plant invlovement)
Complex Tech Transfer
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Tech Transfer (Pilot)
Pilot
Campaign
Tech Transfer (Clinical)
Clinical
Campaign
Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec
Clinical Campaign
Pilot Campaign (10 batches)
Tech Transfer (Clinical)
Tech Transfer (Pilot)
• Early Facility fit assessment
• Length of Pilot Campaign allowed at scale
development
• Early involvement with PGS allowed for Pilot
campaign to be adjusted mid-campaign.
Typical Process Timeline
Complex Process Timeline
(e.g. Biosimilars, In-license assets)
Summary of Ph3 Upstream Development
21Slide courtesy of Olga Mak
Upstream Development
➢ Improved Titer from 0.6 gm/L in 15 days to 2.4 gm/L in 12 days
– Pfizer medium development and feeding strategy improvements
– Seeding Density
– Additional nutrient feed development
Increased Downstream Efficiency
Process Development Addressed Challenges
12,000 L scale purification of 2.4 grams/L harvest
Requirements/ Batch Phase I/II Improved Process
Total Buffer Volume (Liters) 416,000 128,000
Total number of Unit Operations48 12
Downstream Process Time (days)20 6
Slide courtesy of Dick Wright
Tech Transfer to Clinical Manufacturing
• Started the tech transfer process in Feb for Sept runs
– Started early due to # of new raw materials and complexity of process
• Tech transfer modifications:
– Assess storage solutions for columns: Ethanol vs Benzyl alcohol
– Lowered challenge limits for both UFs : (Confirm in Pilot)
– Increased challenge to chromatography steps for flexibility in manufacturing
– New unit operation tested in pilot with direct feedback to manufacturing
– Added lower challenge to column loading range per manufacturing request
Slide courtesy of Christina Pan
Support during Clinical Campaign
• Tech Transfer Team transitions to the clinical manufacturing.
• Person In Plant Program (PIP)
– PIP is fully trained in gowning and suite access to minimize PGS resource
drain
– Actively supports investigations and process troubleshooting
– Real Time Data analysis
• Remote access, sharepoint
• Tech Transfer Governance
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Comparison of Pilot with Manufacturing
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Product quality comparable
Take Home Message
• Complex processes present a unique challenge.
• Start Early!
• (bias alert ☺ )Leverage your Pilot group.
• Encourage communication.
• Encourage transparency.
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Andover Pilot Team
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Acknowledgements:
• Olga Mak
• Dick Wright
• Christina Pan
• Shannon Molloy
• Chris Crowley
• Mary Switzer
• Dave Sullivan
• Arturo Amaro
• Jacob Mauthe
• Rosa Rodriguez
• Brad Volpe
• Cameron Hay
• Mike O’Connor
• Ian Rose
• Greg Porter
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• Bruno Figueroa
• Courtney Bradley
• Mark Kivimaki
• Tiffany Soun
• Amar Shehzad
• Dan Eckler
• Amy Sevigny
• Michael Doane
• Chris Hall
• Sharon Bryant
• Chet Riley
• Shannon McDowell
• Rochelle Walsh
• Ashley Sacramo
• Smit Patel
• Rebekah Ward
• Dave Ripley
• Dawn Eriksen-Stapleton
• Maureen Hoen
• Taylor Kalomeris
• Caitlin Morris
• Kevin Rust
• Neil Steinmeyer
• Martha Jackson
• Adekunle Onadipe
• Robert Murray
• Ashley Slocum
• Jason Just
• Jason Becker
• Mike Cammarata
• Daniel Cummings
• Li Li
• Doug MacLaren
• Darhsan Sokhey
• Georgia Tasiopoulos
• Tim Iskra
• Steven Santora
• Kerstin Crowe
• Maureen Hoen
• Kim Sterl
• Jeff Horne
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