Integrating Continuous and Batch Operations for Efficient Initial Clinical Manufacturing of Biopharmaceuticals

Joseph McLaughlin Pfizer IncBioProduction Summit, 12-13 Dec, 2016

Pfizer’s BioProcess R&D is a Fully Integrated Organization Advancing Projects Across Four Sites

Andover, Massachusetts

Chesterfield, Missouri

Pearl River, New York

Scope of Responsibilities

Cell Line Dev, Cell Culture Dev, Purification Dev, Conjugation Dev, Gene Medicines, Pilot Scale Production

Deliver large molecule drug substance

Provide support from molecular assessment and candidate selection through launch

Close partnerships with Research Units and Manufacturing organizations

Chapel Hill, NC

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Pfizer has a Large and Diverse Biologics Portfolio

Application of Continuous Processing to Early Clinical Supply Protein Manufacturing?

Even breaking rocks can be improved by application of continuous operation, process integration and method intensification

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5

Kleeman Continuous Gravel Crusher with Large Excavators and Hammers

Outline

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1. Process Improvement synopsis

2. Continuous Process Development Collaborators

3. Continuous Vision & Platform process

4. Economic Evaluations

5. Innovation Design

6. Laboratory/Pilot Model

7. Prototype Design

8. Continuous Process Metrics

9. Development Challenges

10.Preliminary Scale-up Strategy

Biological Clinical Manufacturing Process Improvement Synopsis

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~1980’s “Plan for Success”• Clinical manufacturing, regulatory acceptable (safe, effective and pure)

• Process development for impurity identification and control.

• Capital expenditures and CMO partnerships to assure material availability for completion of clinical studies and product launch.

~1990’s “Titer and Yield”• Process development focus on upstream Titer and downstream Yield.

• Excess Capacity as products fail in clinical trials and processes are improved.

• First facilities designed and built with Single Use Application consideration (Solution Storage) to reduce capital.

Biological Clinical Manufacturing Process Improvement Historical Synopsis

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~2000’s “Fast to First in Human”

• Elimination of Clinicial manufacturing as a constraint to new product development.

• High throughput process development, platform processes, accelerated cell line selection and screening.

• Single Use equipment Single use facilities and CMO Partnership form to reduce capital and new facility startup time.

~2010’s - “Continuous Vision” or “Integrated and Intensified”• Clinical manufacturing of numerous diverse products.

• Process development for some focused on regulatory acceptable safe, effective and pure products.

• Others are expedited using platform process development guided by process cost models to balance fixed and variable cost,

• Construction of flexible development and clinical manufacturing facilities for application of diverse operating modes

Continuous Process Development Collaborators

• Boeheringer Ingleheim(BI): – Contract Manufacturer for Batch Single Use Clinical Material

Supply

– Partner in development of iSKID: Integrated continuous single use process and equipment

• CRB, Clark Richardson and Biskup Consulting Engineers, Inc: Economic Evaluations and Initial Design

• Bend Research Contract Research Organization

• Various Academic Consultants

• Pfizer Pharmaceutical Sciences– Analytical R&D, Cell Line Development, Cell Process Development,

Purification Process Development, Clinical Manufacturing

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Research Lead Development Reg MarketedPRECLINiCAL PH1 PH2a PH3PH2b

IDEA Clone

Selection

IND, First In Human

Proof Of Concept

NDA/BLA NME

Continuous Vision derived from an“ End to End” Drug Product Life Cycle perspective

Preclinical Clinical Commercial

Production Bioreactor ProA

Low pH Viral

InactivationAEX VRF UFDF FiltrationExpansion

Continuous Process Vision For Regulatory Toxicology and Phase 1 Clinical Manufacturing

Seed Vial

Drug Substance

Storage

Continuous Process Development Focus

Perfusion Production

CultureCapture pH

InactivationAEX

AEXFlow

Through

SinglePass UF

Platform Batch Process

1111

Formulation & Final Filtration

Store DS

Fed Batch Production Culture

Seed Vial

Wave Expansion

Shake Flask Expansion

N-1 Cell CultureHarvest

Hold

AEXLoad

pH Reduction pH Inactivation

pH Neutralization

AEXColumn

Detergent Viral Inactivation

Harvest Clarification

Capture Load

Capture Column

Capture Pool

Recovery Hold

Ultrafiltration Viral Filtration AEX Flow Through

Filtrate Concentrate

13 Batch Process Steps (6 with multiple cycles)10 Process Holds

Current Platform with Media and Solution Prep

First Economic Evaluation Perfusion Culture

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Perfusion culture higher cost due to increased use of downstream “single use” consumables and labor. Shift

focus to Integrated process

Total

Annual

TAC/Batch or

Perfusion TAC/Gram

$/year

$/batch or

perfusion

campaign

$/grambatches/

year

grams/

batch

Base Case

Production 500L,

Titer = 1.3 g/L, 2 cycles on capture,

1 harvest

100% 100% 100% 24 438

Improved

Batch

Process

8 cycles on capture column 83% 83% 83% 24 438

N-1 Perfusion, Production 500 L

Titer = 2.25 g/L

2 Harvests

136% 149% 75% 22 866

Perfusion Production 100L,

Titer = 0.36 g/L

17 harvests,

205% 290% 273% 17 465

Perfusion

Annual Throughput

Scenario

Capture column operation alternatives

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Perfusion Production Culture

Load 1

Load 2Elute

Capture 2 Column Operation

Perfusion Production Culture

Elute

Accumulate

Load

Surge Tank

Periodic 3 column chromatography also To increase the dynamic capacity

Simulated Moving bed chromatography to provideContinuous elution flow

Surge Tank:

2 Columns:

More Columns:

2nd Economic Evaluation: Capture column

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Total

Annual

TAC/Batch

or Perfusion TAC/Gram

$/year

$/batch or

perfusion

campaign

$/grambatches/

year

grams/

batch

Base CaseProduction 500L,

Titer = 7 g/L, 4 cycles on capture,

1 harvest

100% 100% 100% 23 1000

1 Capture Column +

Surge vessel

100 L perfusion culture,

5 days startup, 7.5 days harvest

at 1 g/L ,

62% 57% 57% 25 1000

2 Capture Columns100 L perfusion culture,

5 days startup, 7.5 days harvest

at 1 g/L, 2 x Capture columns

66% 60% 60% 25 1000

2 Capture Columns +

Improved

Production

100 L perfusion culture, 2 days

startup, 7.5 days harvest at 1 g/L,

2 x Capture columns

77% 55% 55% 32 1000

Annual Throughput

Scenario

Dual Periodic capture column operation selected as more compatible with work to increase upstream productivity

Multiple upstream processes Considered

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Upstream Process

modelsDescription

Bioreactor

Productivity

(g/L BRx/d)

Media

Usage

(L/g)

Fed Batch Fed batch to maximize productivity 0.3 0.5

Continuous Perfusioncell concentration control with stable

permeate & product flow 1.2 2.0

N-1 Perfusion +Continuous

Perfusion

High Density inoculum to reduce

startup time1.6 1.5

High-Intensity Low-Volume

Perfusion (HILVoP)

Multiple feeds to control growth and

maximize bioreactor productivity.

Variable permeate and product flow

1.5 0.5

3rd Economic Evaluation Upstream

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Initial development on multiple upstream options

High Intensity Low Volume Perfusion

Continuous PerfusionFast Start

Continuous Perfusion

Fed Batch

Current Process Development Focus

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Perfusion Production

CultureCapture

pH Inactivation

AEXAEXFlow

Through

SinglePass UF

Seed Vial

Wave Expansion

Shake Flask Expansion

N-1 Cell Culture

Formulation & Final Filtration

Store DS

Ultrafiltration Viral Filtration Filtrate Concentrate

6 Batch Process Steps 1 Periodic Step4 Process Holds

Laboratory/Pilot Model Schematic

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19

Polishin

g

Step

SPTFFSing

le Use

Perfu

sion

Biorea

ctor

ProA

cVI

Media/Feed

Acid Base

SPTFF pool

100 L PerfusionSingle UseBioreactor

Dual Capture Columns Continuous

pHInactivation

Single Pass

Tangential Flow

Filtration

StableIntermediate

Hold

Laboratory/Pilot Model

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100 L Perfusion Single Use Bioreactor, Continuous perfusion or “High

Intensity Low Volume Perfusion”

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Dual Capture Columns

Elution Stream Chamber

pHInactivation

Reactor

Elution Stream Chamber added to de-couple AEX Flow-through

Laboratory/Pilot Model (Continued)

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Laboratory/Pilot Model (Continued)

Single Path Tangential Flow Filtration

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Assembly and operation

Process Flow Diagrams, Process & Instrument Diagrams, Sequence & Valve Device Matrix

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Design a Prototype

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First Prototypes in fabrication

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Apply Metrics

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Batch Next Gen Change

mAb cost(%/batch)

100% ~50% - 2X

Buffer use(L/g)

23 3 - 8X

Bioreactor Productivity(g/L/day)

0.3 1.5 + 5X

Consumables(%/batch)

100% ~40% - 2X

Assay time ~ 1 week 5 min

Proposed Scale Up strategy for Single Cycle Development

• ~0.5 Kg/wk– Clinical Design 100 L Bioreactor, ¼ inch downstream

• 25 Kg/yr– Operate 50 wks/year

• 100 Kg/yr– 4 bioreactors & 4 X¼ inch downstream

• 500 Kg/yr– Scale upstream to 4X500 L Bioreactor 4X¼ inch downstream

• 2000 Kg/yr– Scale upstream to 2000 L Bioreactor – Scale downstream to ½ inch

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Development Challenges

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• Integration, automation and labor savings

• Perfusion filter fouling

• Bio-burden control

• Qualification of reduced residence time for continuous pH virus inactivation

• Data aggregation and analysis for GMPmanufacturing “real time release”

Acknowledgements

Pfizer

• Jeff Salm• Marcus Fiadeiro• Jill Kublbeck• Min Zhang• Mark Chipley• Will Wellborn• Greg Hiller• Matt Gagnon• Bob Kottmeier• Advait Badkar• Rob Fahrner• Jason Starkey• Dave Brunner• Dave Sullivan• Robert Kottmeier

Boehringer Ingelheim

• Raquel Orozco

• Scott Godfrey

• Eike Zimmermann

• Jon Coffman

• Henry Lin

• Avneesh Saini

• Brendan Edwards

• Diana Koulechova

• Anoushka Durve

• Jeff Goby

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CRB

• Phil Lyman

• Eric Unra

• Kory Kaplan

• Tracy Wonnel

• Alejandro Kaiser

Backup Slides

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Plasmid DNA application of Continuous operation

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Pressure Swing Adsorption: Some Processes move from continuous to Periodic

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Pressure swing adsorption has many applications at times replacing Processes such as continuous cryogenic distillation for air and hydrocarbon gas separations

AB

SequenceStartup Pressurization of A with Feed

1.) Pressurization of B with FeedDepressurization of A reverse flow collect Product 1

2.) Purge A collect Product 23.) Pressurization of A with Feed

Depressurization of B reverse flow collect Product 14.) Purge B collect product 2

Feed

Product1

Product 2Similar to Dual Capture Columns

Reference: Adsorption and its Applications in Industry and Environmental ProtectionStudies in Surface Science and Catalysis, Vol. 120A. Dabrowski (Editor) 1998 Elsevier Science B.V.

Other Industries

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Petroleum processes use continuous operations to drive equilibrium controlled reactions with separation, material recycle, and energy recovery

When will Bioprocessing Start using continuous with recycle? Water?

Reference: ELEMENTARY PRINCIPLES OF THE THEORY OF RECYCLE PROCESSES,Author(s): M. F. Nagiev and P. V. Danckwerts1964

Thermal Cracking

Abstract

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Conference: 16th Annual Bioproduction Summit 12-13 Dec 2016 San Diego, Ca

Title: Integrating Continuous and Batch Operations for Efficient Initial Clinical Manufacturing of Biopharmaceuticals

Abstract: Biopharmaceutical manufacturers envision that, as in other industries, continuous processing will provide significant improvement to operations and enable increased global access to medicine. One definition of fully continuous operation is that all inputs, outputs and parameters are at steady state. Konstantinov & Cooney in, “White Paper on Continuous Bioprocessing May 20–21, 2014 Continuous Manufacturing Symposium” identified some of the advantages of continuous manufacturing as reduced equipment size, high-volumetric productivity, streamlined process flow, low-process cycle times, and reduced capital and operating cost. To realize these advantages in an initial clinical manufacturing platform, analysis of individual Unit operations was done in collaboration with contract manufacturer and engineering design partners to define integrated and intensified process options. The mode of operation of each step from vial thaw, through expansions, production culture and purification to product packaging was considered for continuous, transition, periodic or batch operation. This Presentation describes the use of deterministic process modeling to guide process definition, prototype assembly and operational testing.