Next Generation Biopharma Manufacturing Facilities

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Next generation biopharma

manufacturing facilitiesTrends for biotherapeutics and their production

PABME, Dubai, April 29 2008Dr. Gnter Jagschies, Senior Director R&DStrategic Customer RelationsGE Healthcare Bio-Sciences ABUppsala, Sweden

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Overview

Pressure on pipeline efficiency and cost of treatment

Focus on manufacturing efficiency and costs

Varying API categories and production sources

Widely varying production scales

Switch from dedicated to multiproduct facilities

Flexibility, agility, cost efficiency


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Top selling biopharmaceuticals 2007

FVIII, F VIIYesNovo Nordisk, Wyeth, Bayer, Baxter 4,518Clotting factors

MabYesGenentech 5,527Rituxan / MabThera

VaccineNoMerck&Co 1,481Gardasil

MabYesMerck-Serono, BMS 1,439Erbitux

Mab fragmentNoGenentech, Novartis 1,386Lucentis

1,144

>1,200

2,439

2,762

3,000

3,605

4,114

4,277

4,862

4,948

5,275

8,223

10,926

11,101

US $ M

MabYesAbbott Laboratories Humira

Growth

No

Yes

No

No

No

Yes

Partly

Yes

Yes

Yes

Partly

No

Yes

Mammaliancells

ErythropoietinAmgen, Roche, J&JEPOs

MabJ&J, Schering-PloughRemicade

Fc fusion proteinAmgen, WyethEnbrel

rec hInsulinEli Lilly, Novo Nordisk, Sanofi-AventisInsulins

LMW HeparinSanofi-AventisLovenox

Glucocerebrosidase

Mab

Vaccine

rec hGH

Mab

G-CSF

Mab

alpha/beta-Interferon

Substance

GenzymeCerezyme

MedImmuneSynagis

WyethPrevnar / Prevenar

Pfizer, Novo Nordisk, Eli Lilly, SeronoGrowth hormones

GenentechAvastin

AmgenNeulasta / Neupogen

GenentechHerceptin

Schering-Plough, Roche, Biogen IdecBayer-Schering, Merck-Serono

Interferons

Companies countedBranded productProduct category

Biopharma blockbusters 2007: US $ 82,3 billionMab blockbusters 2007: US $ 26,5 billion




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Cost of treatment, example

0

5.000

10.000

15.000

20.000

25.000

Today -10% -20% -30% -40% -75%

Typical current level

Level of new or

established alternative

?

?

?

Future level?

Market forces:- Public health care systems- Shorter time to next innovation- Biosimilars




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New(?) Challenges

Flexibility

AgilitySpeed

Efficiency




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Source: Genetic Engineering News, 2002

20%

32%

6%

6%

3%

13%

20% Depreciation

Labour

Media

other Raw Materials

Protein A resin

other Consumables

Insurances, Taxes,

Maintenance

D

C

I,T,M

RML

M

Production EconomicsOperating Costs in Mab Production




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What is best-in-class performance?

Best in class performance isfoundation for the future

ac y u za on = -

Cost = 15% CoS (100 USD/g)

Process yield = 70-80%

Product titer = 5 g/LTime = 10 day upstream

2 days downstream


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Mabs, rProteins, Vaccines, Cells, Genes

2006 2004Pharmaceuticals Research & Manufacturing Association

(PhRMA) clinical trials summary (2004-2006):Mabs: 76 160

rProteins: 57 94

@ success rate: 20% > 50 approvals by2012



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Mabs and mammalian cells dominate(only products / API categories > US $ 1 billion included)

26.500

51.900

3.920

Mabs

rProteins

Vaccines

51.484

30.800

Mammalian cells

Other cells





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Biopharma production challenges(Production volume and revenue map, 2006 data)

Pharmacy list prices 2006, available packages:Arzneimittelkompendium (CH), MediMedia Gelbe ListePharmaindex (GER), RxUSA.com Pharmacy (USA)

Annual global sales 2006: Annual reports 2006 Plasma products: Marketing Research Bureau 2004

1

10

100

1.000

10.000

100.000

1.000.000

10.000.000

100.000.000

0,01 0,10 1,00 10,00 100,00 1.000,00 10.000,00 100.000,00 1.000.000,00

Annual production volume [kg]

Pharmacypricevalue[USD/g,2006]

HSA, plasma

Huminsulin

Rituxan/MabThera

HumalogAvastin

IVIG, plasma

EnbrelHumira

RemicadeHerceptin

SynagisPulmozyme

NeulastaReoPro

Aranesp

ReFacto

Neupogen

BeneFIX

KogenateAvonex

PegaSysRebif

NovoSeven

Humatrope

Xolair

Advate

Coagulation factor VIII EPO, Factor IX, VII, interferonsl HGH, low dose antibodiesn High dose antibodies, fusion proteins Insulinsr Plasma proteins

Most future Mabswill require annual

capacity of 100-500 kg

Some Mabswill require annual

capacity of 1-5 tons

Insulins

1-5 tons

Plasma proteins50-500 tons

Most rProteinswill require annualcapacity of 1-10 kg





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The challenge is the supply of vaccines

Capacity Time

0

500

1000

1500

2000

2500

milliondoses

2006 PandemicPlanning

There is a huge gap between the expecteddemand and the current capacity Most countries are looking for in-country

domestic solutions WHO is driving local capacity build up

20102004 WHO

Currently the manufacturing timeis ~6-9 months Need of faster supply less than 3 months

production time Difficult and time consuming to scale up with

old technology





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The vaccine landscape is changing and is

moving to new manufacturing methodsEgg-basedproductiontechnology

Cell Culture-basedproductiontechnology

Cell Freeproductiontechnology

System Eggs Mammalian Cells Insect and Bacterial Cells Recomb Cells

Lead Times 6-9 months ~6 months ~3 months Days?Maturity On the market New on the market In 2-4 years time -





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Many facilities have

brand new installations and up to 25year old installations, running with newand old processes.

dedicated one-product or multi-product setups.

a degree of mismatch betweencurrent bioreactor output and DSP line

dimensions chosen at the time of facilitydesign.

limited flexibility!

Large / modern biopharma facilities

Genentech, Oceanside, CA

Image: Boehringer Ingelheim GmbH





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Production setup: 6 fermentors 1 DSP

Mab Cell Culture(6x 2.000 L, 5 g/L)

Cell Removal

Capture(1x 120 cm , 30 cm height)

Polishing 1(1x 80 cm , 25 cm height)


UF/DFFormulation

Virus Removal

Virus Inactivation

Mab Cell Culture(6x 15.000 L, 5 g/L)

Cell Removal

Capture(1x 160 cm , 40 cm height)



UF/DFFormulation

Virus Removal

Virus Inactivation

- 313 L bed volume- 40 g/L capacity- one cycle

- 780 L bed volume- 40 g/L capacity- three cycles

10-ton/yr

scenario

1-ton/yr

scenario





10 kg/batch126 batches

80% yield

75 kg/batch168 batches

80% yield

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Cell cultureDocumentsPDFComplete




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Chromatography

CD = 80cmCD = 100cmCD = 120cmCD = 140cmCD = 160cmCD = 180cm

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Stainless steel space

Disposables space

Emerging production scenariosMore companies will have more than one product in production, many of them small in scale

Batches / product / year(scale: 1-170 with six-pack of bioreactors)

Bioreactorvolume

(scale:525000L)

Scale limit for many single-usecomponents: 1000 L

Large number of batchesfavors re-use strategies

10 100

10

100

1000

10000

cGMP fully dedicated facility(500-3.000 kg per product)

cGMP clinical manufacturing(2-30 kg per product)

cGMP multi-product facility(10-500 kg per product)cGMP multi-product facility

(10-500 kg per product)cGMP multi-product facility(10-500 kg per product)

Non-GMP pilot facility(10-500 g per product)

High product titers smaller installationsproduce largequantities

How much of GMP productionwill reach the disposable space?

Product ion sc enar ios n eed tocon sider higher degrees of f lexibi l i ty

High product titers fewer batches producelarge quantities

Lab bench designsused to be a

production transferissue.

Now the issue is

with stainless steel

engineer ing habi ts!


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Reality checkHow many products are sharing facility capacity?

Products above one metric tonper year may still require oneor more dedicated facilities

Multiple product facilities willbe dominating the future

Flexibility in the design is bestprotection against uncertaintyin planning

Genentech manufacturing backgrounder (www.gene.com, 2006)


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LEAN chromatography - summaryClassic step (1st generation tools)

Improved step (use of up-to-date tools)

Value adding work

Non-value adding work

Required non-value adding work

Optional:Waste removed

Single-useoperation

Resin preparation*) Packing andre-packing*)

Excessive equilibration volume &)

Excessive elution volume &)

Excessive process time &) &) not optimized

Run

CIP and storage #)Equilibration Load Wash Elution Strip

Inefficientwash step &)

Resin Preparation*)

Run

CIP and storage #)Equilibration Load Wash Elution Strip

Packing andre-packing*)

Excessive equilibrationvolume &)

Excessive elutionvolume &)

&) not yet optimized

Inefficientwash step &)

ReadyToProcessTM

pre-packed

pre-qualifiedpre-sanitized

PreDictorTM plates(HTPD)

Fast,low cost

optimization(LEAN & SixSigma)

AxiChromTM

Faster procedureLess failure Modern resins

Higher capacityand flow, longer

lifetime


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Influenza vaccine production capacity buildup with disposables to save time

Traditional Flu Vaccine Production Facility Commissioning & Validation:

Build Facility

Validate Equipment

Commission Facility

Validate Process

Build Facility

Validate Equipment

Commission Facility

Validate Process

Time Saved

Saving ~60%

in time

Disposable Insect Cell Culture-Based Flu Vaccine Production:


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flexibel planning

flexible location

minimal capital investment

minimal process development

minimal distribution and storage local policies/relationships

local human capital

Our vision . . .the future is a modular, self-supporting, disposable production plant

Fast deployableproductioncapacity


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Process economy gains overall DSPUse of modern resins: combined effect of capacity, flow, and lifetime

10,911,8

19,2

37,4

0

5

10

15

20

25

30

35

40

Classic process Protein A update Protein A 3-step

model process

Protein A 2-step

model process

Downstream

costcontribution[USD/g]

0

20

40

60

80

100

120

DSPprocesstime[h]

Cost savings with modern resins up to 70%Process time down to 2 days from 5 days

2-step process: additional indirect gains fromspace and tankage requirements

Working volume 10,000 LTiter 5 g/LYield 79%

(Sepharose Fast Flowresins)

(MabSelect SuRe/CaptoS/ CaptoQ)

(MabSelect SuRe/Sepharose Fast Flow)

(MabSelect SuRe/Captoadhere)


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Process improvements

FacilityLow utilization Intense

Efficiency gains directly visible at management levelEfficiency gains hardly visible at management level

Investment in improvement pays off quicklyHesitant to invest in improvement

Equipment performance on critical pathExisting equipment, performance tolerance

Staff is a scarce resource, tough prioritizationStaff is available and has spare time

Intense facility utilizationLow facility utilization

Can be nothing Can be millions

Cost driven management Extra production time creates the opportunity to run more batches.

In a facility that produces several Mab products at a cost of $ 100M 70% of the costs may beconsidered fixed. At 5 days batch time up to 70 batches of 25 kg each could be run. One additionalbatch would reduce the cost per batch with $ ~15K. The savings amount to $ 1M / yr.

Revenue driven management At a commercial value of $ 2.000/gram, one extra batch of 25 kg of product would be

worth $ 50M of extra revenue.


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Conclusions

Monoclonal antibodies Improved processes with modern production tools and LEAN design are

requirements to remain competitive and meet treatment cost challenges

Insulin Diabetes is a growing challenge all over Asia. Local production will be a need

and a business opportunity

Plasma proteins Advanced healthcare is a growing need all over Asia. Again, local collection of

human plasma and fractionation is a business opportunity

Vaccines Vaccination carries the hope for cure instead of chronic treatment. Infectious

disease is a global threat (e.g., pandemic influenza). Short lead times of just afew months require fast deployment of production where the outbreak is.

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Thank you

GE Healthcare Bio-Sciences AB, a General Electric company.

GE Healthcare Bio-Sciences AB

Bjrkgatan 30751 84 UppsalaSweden

Capto, MabSelect, and Sepharose are trademarks of GE Healthcare companies. Biacore is atrademark of Biacore AB.GE, imagination at work and GE monogram are trademarks of General Electric Company.

All goods and services are sold subject to the terms and conditions of sale of the company within GEHealthcare which supplies them. GE Healthcare reserves the right, subject to any regulatory andcontractual approval, if required, to make changes in specifications and features shown herein, ordiscontinue the product described at any time without notice or obligation. Contact your local GEHealthcare representative for the most current information.

2007 General Electric Company All rights reserved.

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Next Generation Biopharma Manufacturing Facilities

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