adapting tech transfer to non-platform...

Adapting Tech Transfer to non-Platform

ProcessesCase Study

JOHN COYNE SR MANAGER ANDOVER PILOT PLANT

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Case Study


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Adapting Tech Transfer to Atypical Processes

Case Study


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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


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


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


Process Development Balancing Act

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Cost Quality


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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Pilot

Campaign


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)



• 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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