Chugai Next Generation Factory Concept:Implementation of Continuous Manufacturing Technologies to Bio Pharmaceutical DS Manufacturing

CMC strategy forum Japan2018.12.04

CHUGAI PHARMACEUTICAL CO., LTD.Yasufumi Ueda, Ph.D

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Contents

Introduction Chugai Next Generation Factory Concept Enabling Technologies and Preliminary Data Hurdles Need to Overcome

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History of Chugai Bio API manufacturing

Single Use facility

10kL x 2 (2002~2010)

2.5kL x 4(1990~)

1990 Epogen ® JP launch

2005 Actemra® JP launch(CD)

2010 Actemura® US launch(RA)2009 Actemra® EU launch(RA)

1994 Granocyte® EU launch

1991 Neutrogin® JP launch

10kL x６ (2006~)

2kL x 2 (2013~)2kL x 2 (2015~)

Early and Late stage clinical and commercial mfg

2011 Actemra® site addition (RA)

4 2(2016~)

2008 Actemra® JP Applicaition Expansion(RA)

Over 25years, more than 2000 lots !

2013Actemra® SC launch(RA)

Large Stainless facility

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Current Chugai BiomanufacturingFacility Portfolio

Single useflexible facilityfor multi products in clinical phase Multi product facility

for small to middle scale various demands

Dedicated large scale facility for high demand product

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New Concept of Production

“Next Generation

Factory”

Cost Pressure

Market Globalization

Demand Variability

Innovative Technology

Current situation and Future challenge facing Biologics production

Ultra-Low Cost Manufacturing for High-variety & Low-amount of Products

• Bio science and technology (Target integration, single-use, etc)

• ICT (Big data, AI, etc)

• Precision and Personalized healthcare

• Various target & molecular formats

• Medical financial difficulty• Severe competition (e.g.

Bio-similar)

• Global supply chain• Emerging market

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Scope of Next Generation Factory

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Target Process for NGF, “End to End”Adopt continuous process for fermentation, purification, and Drug Product filling,together with In-line testing for automated process control and real-time release.

“End to End” seamless production from raw material to finish product release

Reduced number & size of equipment, and operators.

Current Process（Fed-batch Culture/Batch Purification）

NGF Process（Perfusion Culture/Continuous Purification, DP)

Fermenter Scale2000 L x 3~6

Fermentation & Harvest Purification

Fermenter Scale (Single-Use)500 L

Batch Process Flow Chart

Column Diameter40~100 cm

Column Diameter (Pre-pack)5~10 cm

Continuous Process Flow Chart

Tank1Tank2Tank3

UF/DFPolish2

Culture

CaptureHarvest

CultureHarvestCapturePolish1UF/DF

Ferm. Harvest Purification Filling

Filling

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Concept of NGF

Manufacturing amount per year (kg)

Manufacturing cost comparison

10000 L Stainless Steel

Lowering cost , while increasing speed and flexibility

2000 L Single Use500 L NGF

Man

ufac

turin

g co

st (U

SD /g

Mab

)

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Target numbers of NGF

Low cost manufacturing $100~$400/g → $10-$50/g Delay decision-making on capital investment Fit production scale at right time depending on business environment

Low initial investment Short construction period Low running cost Demand flexibility

1/4 1/2 1/3UK3 $336M → NGF $75M UK3 36M → NGF 12-18M

10-1000 kg/y

ModularSmall ProductivityModular design with ‘box in box’ reconfigurable factory concept

Scale down the facility sizeSmaller equipment, smaller footprint

Batch to continuousHigher productivity in smaller facility

Automation and reduce FTEs

Right decision, right time!

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Examples of Enabling Technologies

In-line monitoring

Orchestration system

Demand monitoring

Automation

Robotics Multi-column chromatography system

Perfusion culture

Cell line development

Real time release

Data management system

ICT AI

PAT

Continuous filtrationContinuous UFDF

Continuous virus inactivation

Single use

Modular facility engineering

In-line conditioning

We are looking for corroborative partners who have advanced technologies in various fields and cooperate to build NGF with us.

Media development

Novel purification material and device

Direct DP Filling

>> Case Study

Buffer management

>> Case Study

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In-house Case Study of Perfusion Cultivation

0

20

40

60

80

100

0

200

400

600

800

1,000

0 4 8 12 16 20 24 28 32 36 40 44

Viab

ility

(%)

VCD

(×10

^5 c

ells

/mL)

Capa

cita

nce

(pF/

cm)

Cultute time (day)

Cell growth result of 1L scale perfusion culture

Target by 20204-5 g/L/dayCurrent

average 1-2 g/L/day

Medium development

Cell line development

Culture method optimization

We have successfully maintained the viable cell density at 700x105 cells/mL for 45 days in a 1 L scale perfusion cultivation system. We are aiming to increase productivity up to 4-5 g/L/day by 2020.

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Continuous5-column system

Continuous3-column system Batch

System

Resin MabSelect SuRe pcc MabSelect SuRe pcc MabSelect SuRe

HCCF conc. 9.16 g/L * 9.29 g/L * 2.03 g/L

Column height (vol.) 2.5 cm x 5(5 ml x 5)

2.5 cm x 3(5 ml x 3)

20 cm(15.7 ml)

Load Flow rate 270 cm/h 150 cm/h 150 cm/h

IgG binding capacity 62 g/L resin 60 g/L resin 30 g/L resin

Yield** 91% 87% 93%

Number of cycles 378 cycle/day(75 cycle/1 column)

176 cycle/day(58 cycle/1 column) 7 cycle/day

Purification amount 4.7 kg IgG/L-resin/day

3.5 kg IgG/L-resin/day

0.21 kg IgG/L-resin/day

Multicolumn chromatography for Protein A affinity step * concentrated by SP-TFF

X 22

22 times higher productivity was demonstrated by implementing BioSMB, MabSelect SuRePCC and SP-TFF.

in-house data

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Technical Hurdles in NGF concept

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• Is Surge Tank necessary ?• How to integrate and control all steps inc.

IT and PAT ?• How to implement virus inactivation step ?• Is MCCS necessary for the polishing steps ?• How to implement filters to remove

precipitation ?

Chrom.1 Chrom.2

Concept of

Surge Tank

Konstantinov and Cooney, ISCMP 2014

whitepaper 4

How to connect USP and DSP, and each DSP steps ?

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• How to manage max capacity load in scale-down model ?

• Does this twin model work ?

Or?

How to set up Scale-down model for MCCS to validate the process ?

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Continuous virus filtration

VF step is difficult to be scaled down in continuous process (e.g. filter changing, sanitization, Integrity test…)

Enough membrane size is necessary to be operated in continuous process without filter changing

Is this switching idea

acceptable ?VF by TFF ?

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UF/DF & Conditioning

Continuous way with single pass TFF and in line DF disposable devices

Semi-continuous way with conventional UF filter Automated conditioning system with PAT

Which way is simpler and more cost effective?

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Technical Regulatory Hurdles in NGF concept

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State of Control and unit operation

• How can we define and manage ‘State of Control’ ?• How to manage rejection from the process ?• Definition of ‘Batch’ and ‘Lot’• Relating to PAT （online monitoring)… Is IPC necessary ? Is DS release testing necessary (if DS and DP conducted

continuously) ?

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Virus safety and virus clearance study design

• How to define maximum cultivation days (CAL study) ?• How to perform virus inactivation step ?• How long will we perform VF study ?• How much samples do we need to prepare enough virus

spiking material ?• Can virus be active and keep good quality during whole study

time ? • Do we need laboratory-scale MCCS in CRO ?

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Other Thoughts…

• How to implement additional factor ‘Time’ for process validation and characterization study ?

• More strict bioburden and endotoxin control with ‘Time’• Single use equipment reliability (with ‘Time’)• System complexity (a lot of valves and total control) and

durability (periodic maintenance frequency and contents）• Documents Batch record contents (set-up, monitoring, IPC item,

release item) How does CoA look like ?

• OOS and trouble control (no way of return and no rescue ?)

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We are still have a lot of ‘How’ questions but….

• International Symposium of Continuous manfaucturing of Pharmaceuticals 2014 white paper 4： Published

• BPOG continuous bioprocessing roadmap white paper (https://www.biophorum.com/)： Close to be published

• A-Mab Continuous bioprocessing QbD：Will be Published on 1Q 2019

• ICH Q13 Working group• JPMA, AMED, PMDA, J-PDA, FDA etc…

Currently a lot of working groups and white paper

preparation regarding continuous manufacturing is

on going and it will help us a lot !!!

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Thank you for your attention !Do you have questions and comments ?

Rheinfall in

Switzerland

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Appendix

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Biomanufacturing trend and perspective

SpeedCost Flexibility

Payer Cost Pressure Precision and Personalized Medicine

Outcome pursuance Biosimilars

Severe competitionEmerging markets

Non IgG new type products

Demand variability

NGF, Next Generation Factory

Scale Distributed

Large scale stainless steel bioreactor Middle scale single use bioreactor

20 years ago 10 years ago to present

- Low titer < 1g/L- Normal IgG- Block busters- High demand - Stainless steel- Dedicated facility

- High titer 5-10 g/L- Engineered antibody- Rare disease - Low demand - Single-use technology- Multi-product facility

Cost Pressure, Uncertainty, Technology Advancement and Market Growth

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Perfusion Cultivation■Supply media in constant speed and extract the same amount of Perfusate■Keep the cultivation status as consistent and the cell produce MAbcontinuously ■Productivity/Time is high

Media

Cell bleeding FiltrateMAb

Cell retention device

Perfusate(Cell+MAb)

Perfusate(Cell)

Sen Xu, Biotechnol. Prog., 33:867–878, 2017

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Mono Column Multi Column

PoolLoad

Equibration

Elute

Regeneration

Waste

Waste

Waste

Multi Column Chromatography System (MCCS)

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