the nevoline™ system: intensification & integration of

Biomanufacturing, smart engineering and process intensification expertise©2019 Univercells. All Rights reserved

Thomas Theelen, Business Development Manager

NON CONFIDENTIAL

The NevoLine™ System: Intensification & Integration of Processes in a Low-Footprint, Automated Platform

BPSA European Advisory CouncilF2F Meeting | June 25, 2019

2

Contents Page

©2019 Univercells. All Rights reserved

A. Need for large quantities of affordable vaccines 3

B. The main barriers 7

C. NevolineTM, the Univercells manufacturing solution 12

D. The future of Nevoline™ manufacturing platform 30

E. Q&A

A. Need for large quantities of affordable vaccines

4©2019 Univercells. All Rights reserved

Vaccines are an effective intervention reducing mortality caused by infectious diseases

Source: WHO

2-3M

Deaths prevented

26

Diseases preventable

85%

Vaccination coverage

1.5M

Additional lives

by immunization every year

by vaccines remaining constant could be saved every year by increasing

immunization globally

Rabies still claims 59,000 human lives annually (100% fatality)

Measles is a leading cause of death in young children, causing 90,000 deaths in 2016. Vaccination has prevented 20.3 m deaths 15 years


Vaccines are one of the most cost-effective healthcare interventions ever invented

Poliomyelitis cases after vaccines introduction

Sources: http://www.post-polio.org/ir-usa.html; CDC's Summary of Notifiable Diseases, US, 2003; MMWR, Vol. 52, No. 54, 2005

> The introduction of vaccination led to a drop of poliomyelitis cases within a few decades

> Only global immunization campaigns can lead to polio eradication

1935 1940 1945 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 2010

15,000

5,000

0

35,000

10,000

20,000

25,000

30,000

40,000

55,000

45,000

50,000

60,000

Poliomyelitis total cases

Paralytic poliomyelitis cases

Non-paralytic poliomyelitis cases

1955: Vaccine Salk IPV

1961: Vaccine Sabin OPV

Poliomyelitis reported cases after IPV and OPV vaccines introduction (USA, 1935 - 2008)

http://www.post-polio.org/ir-usa.html

6©2019 Univercells. All Rights reservedSource: UNICEF

Large procurement organizations face supply shortages despite contracted commitments, resulting in substantial supply gaps

Supply gap – Example Polio

> The risk of the consolidated supplier base turned in a threat

> Committed supply targets are not met by the vaccine manufacturers

> The result is a supply gap for IPV of around 50 million doses/year

> Need to increase capacity and decrease costs

Long term arrangements vs. actual and forecast supply 2014-2018

0

20

40

60

80

100

120

2016 20172014 20182015

Actual 2014-2017/Forecasted 2018

Long term agreement

Summary of awarded and unawarded quantities for 2019 to 2022

Tender demand

Initial awards

Unawarded quantities

2019 2020 2021 2022 Total

112,800,000

41,500,000

71,300,000

69,380,000

51,500,000

17,880,000

134,500,000

49,500,000

85,000,000

452,830,000

212,000,000

240,830,000

136,150,000

49,500,000

86,650,000

Quantities (doses)

B. The main barriers


The majority of viral vaccines are still manufactured with "outscaled" lab-scale principles resulting in high CAPEX

Source: Univercells

T-Flasks Roller Bottles Eggs

Vaccine manufacturing today

©2019 Univercells. All Rights reserved 9


> Barrier: High CAPEX

> Risk: High number of ascepticmanual operations

> Production capacity↓↓ ,cost ↑

Source: Univercells

At least 80% of viral vaccinemanufacturing techniques are still based on lab-scale principles "outscaled" to manufacturing scales

©2019 Univercells. All Rights reserved 10


Source: Univercells

When vaccines are produced in large bioreactors in more modern facilities, capacities are increased BUT at a very high CAPEX

> Barrier: Very highCAPEX

> Reduced risk: Limited ascepticmanual operations

> Productioncapacity↑↑ ,cost↑↑

11©2019 Univercells. All Rights reservedSource: Univercells

Technology-driven affordability

Bar

riers

to b

iop

rod

uct

ion

1

2

CAPEX intensive (EUR ~100-300 m)

High operational costs preventing competitive pricing


> Provide mass production of viral vaccines, with a dramatic decrease of CAPEX and at a record CoGs per dose, for those vaccines to be available and affordable for LMICs

> NO compromise on quality

> Make sure this goal would be achieved without economies of scale and without counting of low salaries

C.Univercellsmanufacturing solution


Univercells technology combines process intensification and chaining, delivering high-performance process achieving low CAPEX/OPEX

Source: Univercells

INTENSIFICATION – small is BIG

Well established principle of biomass immobilization for waste water treatment …

… applied to vaccine manufacturing results in

a dramatic decrease of bioreactor size


Univercells technology combines process intensification and chaining, delivering high-performance process achieving low CAPEX/OPEX

Source: Univercells

CHAINING – never store intermediate volumes, treat inline


scale-X™ bioreactor product range will offer viral production capacities from laboratory R&D to GMP commercial production

Bioreactor product range

Source: Univercells

2002.4 600

Integration in NevoLineController

Growth surface [m²] 10 30

Benchtop

controller manufacturing system


scale-X™ bioreactor product range will offer viral production capacities from laboratory R&D to GMP commercial production

scale-X carbo & scale-X nitro bioreactors

Source: Univercells


scale-X™ bioreactor’s proprietary fixed-bed structure delivers high-quality production of viral particles

Proprietary fixed-bed structure delivers high-quality production of viral particles

Structured packing of rolled membrane> Unique dual layer structure

> Ensuring homogeneity & reproducibility of the culture:

– In cell entrapment & distribution

– In media circulation & nutrients availability

> Adapted to a variety of cell line & viral products

High density & homogeneity

Product concentration & product release features

> Enhanced recovery of viral particles


The fixed-bed structure allows a fast cells entrapment and a homogeneous scalability

Rapid and homogeneous cell entrapment

Benefits of a structured bed

0,00E+00

1,00E+08

2,00E+08

3,00E+08

4,00E+08

5,00E+08

6,00E+08

7,00E+08

8,00E+08

Inoculation Inoc +1h

> Homogeneity – scale up virtually non limited

> Fast cells entrapment/attachment

> Easier to fabricate – cost effective

> Compatible with multiple bioreactors

Cell Entrapment Kinetics


scale-X™ consistently achieves high cell densities on a small footprint for several cell lines

scale-X hydro | Cell growth examples

Experiment 1, Serum (N=30)

Experiment 2, Serum Free (N=10)

> Reproducible cell growth

> High cell density at infection:

200,000+ cells/cm², or ~30 M/mL

> Reproducible cell growth

> High cell density at infection:

650,000 cells/cm², or ~100 M/mL

> Fixed-bed works as a filter, making it

compatible with non-adherent cells

> High cell density at D10:

1,300,000 cells/cm², or ~200M/mL

> Fed batch regime for mAb production

> Vero – Influenza, Newcastle, Rabies, Rotavirus

> MRC5 – Hepatitis A

> MDBK – Bovine Herpes Virus

> CEF – MVA

> A549 – rAAV, Adenovirus

> HEK 293 – Adeno, AAV, Lentivirus, Retrovirus

Other biological

systems grown

in fixed-bed


The NevoLine™ low-footprint system integrates the result of four years of development and implementation

Early concept

20142015



Further prototype

20162017


Assembly of NevoLine at Univercells

Oct.2018

Source: Univercells



January 2019 – Installation of NevoLine at Batavia Biosciences

The NevoLine™ platform with scale-X™ 600 m² integrates the result of four years of development and implementation

2017

USP & DSP development –

Advanced prototype

2016

Project

Initiation with BMGF support

2018

NevoLine finalized @Univercells

2019

Process scale-up USP, DSP, Inactivation

2020+

Ready for GMP operations at commercial-scale

2014-2015

Early concepts & prototypes


Conventional sIPV production on microcarriers presents several challenges with complex operations impacting time and costs

Challenges of sIPV production with microcarriers

Source: Univercells

PV infection & production

BR Harvest Clarification Concentration1st chrom

step2nd chrom

stepBuffer

exchangeFormulation

Dilution & inactivation

Stainless Steel facility, Batch-based process

Process time: USP

DSP

4-5 weeks

> 3-4 days

Capacity (doses/year) 50 million

Footprint (m2) > 5,000

CAPEX (million USD) 100 - 300

CoGs (USD/dose) 1.2 - 1.5

Preculture -1 Preculture -2 Preculture -3 Preculture -4 Preculture -5 Cell Prod BR Trypsinization Trypsinisation


sIPV production based on the NevoLine™ manufacturing platform integrating the scale-X™ bioreactor

sIPV production with NevoLine platform

Source: Univercells

NevoLine process with scale-X 600m²

Process time: USP

DSP

3 weeks (instead of 4-5 weeks)

1 day (instead of > 3-4 days)

Capacity (doses/year) 50 million

Footprint (m2) ~1,500 (instead of > 5000)

CAPEX (million USD) < 30 (instead of 100 - 300)

CoGs (USD/dose) < 0.3 (instead of 1.2 - 1.5)

> High cell density, small footprint bioreactor with in-line harvest and continuous concentration

> In-line single step purification

> All steps chained and integrated into small footprint cabinets –isolators or biosafety cabinets

High performance, single-use fixed bed bioreactor> Intensification of cell

culture and viral production process

> Drastic reduction of footprint

> Enables process chaining and integration into contained cabinets

(Batavia Biosciences)

Highly intensified production process for sIPV


NevoLine™ system is suited for commercial-scale production of viral vectors for gene therapy applications, first application for AAV

NevoLine for AAV production

Source: Univercells

Culturescale-X™ fixed-bed bioreactor,

In-line product concentration

PurificationDepth filtration & bioburden filtration,

Chromatography

FormulationTangential Flow

Filtration

Containment & safetyOperations in biosafety cabinets

Automated operationsensuring high containment & safety

Modular setupAdaptable to different types of viral vectors

Cost-effective production> Low CAPEX & COGS

> Simplified infrastructure


Novel bioproduction model transformingvaccine production economics

NevoLine™ represents the next generation of vaccine manufacturing, transforming production economics & global access

Simplified equipment & facility

Source: Univercells

Production equipment Facility

Intensified & contained for reduced footprint & CAPEX

Simplified infrastructure6-fold footprint reduction

Con

vent

iona

lpr

oces

s

Complex process & equipmentHigh investment & operational cost

10,000 m²

1,500 m²

Impact

Nev

oLin

epr

oces

s

* Target values, scaled-up process under development


Univercells is currently “prototyping” its modular facility approach in Nivelles-Belgium, for its new viral vaccine development lab

Source: Univercells

Modular facility installation | 6 February – 26 April 2019


Univercells technology enables manufacturers to achieve industrial production at lab scale, low cost and in a record time

INTENSIFICATION and CHAINING, base of Nevoline platform

Delivers low CAPEX & COGS

> Step change in manufacturing scale and yields significantly

reduces COGS

Industrial production at lab scale

> Highly intensified process allows miniaturization of commercial

manufacturing

Flexible, low footprint, rapid deployment> Can be implemented in new or existing facilities

> Factory operational in few months

Broadly applicable to viral processes

High Containment and safety

1

2

3

4

5

Platform and concept

D. Future ofmanufacturing platform


Towards zero human intervention to increase consistency and reduce risk

Vision at Univercells

Source: Univercells

Vis

ion

> Vision under construction

> Constitution of a consortium

> First prototype by 2022

> Integration of analytical assays

> Re-develop some analytical assays

> Integration of robotics for execution of analytical assays and sampling

> Data acquisition, processing and supervision – cloud computing

Main evolutions



Illustration in a med-tech company

Source: Univercells


“Humanity’s greatest advances

are not in its discoveries, but in

how those discoveries are applied

to reduce inequity.” – Bill Gates

Acknowledgements

C. Yallop

A. Hamidi

W. Moya

Source: Univercells

http://www.google.es/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwim2Jey28PWAhWSKVAKHbbwCjQQjRwIBw&url=http://www.gavi.org/about/partners/bmgf/&psig=AFQjCNHGqmxmUyCyS14fAWs3gOtRX9g5MA&ust=1506544938899179

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