Du laboratoire à l'usine du futur : gestion de l'innovation dans l’industrie pharmaceutique par...

Edith Lecomte-Norrant, Business Excellence / Innovation & Technology & Sciences Director, UCB BioPharma

Jeudi 2 juin

Du laboratoire à l'usine du futur : gestion de l'innovation dans l’industrie pharmaceutique.

Liege Creative, en partenariat avec :

From laboratory to manufacturing plant of the future…

June 2nd 2016

E Lecomte Norrant

UCB /Pharma Sciences/ Innovation-Technology-Sciences Dr

E Lecomte Norrant LiegeCreative June 2nd 2016

ן UCB BioPharma: a short description…

ן Context : Why Innovation? where are we? Where do we want to go?

ן Innovation: a complex interaction between multiple areas…

ן The laboratory of the future: my own vision …

ן My own experience concerning “The laboratory of the future in pharmaceutical area” Chemical and biological process with new innovative tools

ן The manufacturing plants of a close future

ן Conclusion : the future starts now…

OUTLINE

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Management of Innovation… in the laboratory of the future to the manufacturing plant of the future?

UCB: making lives better every day 3

Bringing solutions to people living with neurological or immunological diseases

Key facts and figures (2015):

■ Revenue: €3.88 billion

■ rEBITDA: €821 million

■ More than 7500 employees globally

■ Operations in ~40 countries

■ R&D Spend: 27% of revenue

■ Listed on Euronext

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UCB, One Global footprint

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2 Research sites: UK, BE 8 Manufacturing sites: US, IR, BE, CH, India, China, Japan

40 commercial sites (Mexico, Brasilia, Atlanta, London, Paris, Milano, Mumbai, Tokyo,…)

UCB: reinventing itself, leveraging a solid heritage 5

1928: Emmanuel Janssen establishes

UCB in Brussels

1972: A new state-of-the-art R&D

center in Braine-l’Alleud, Belgium

1980s: UCB registers its novel

antihistamine Zyrtec®

1990s: approval of Keppra®, a novel

anti-epileptic

2004: UCB acquires British

biotech company Celltech

2006: UCB acquires German pharma company Schwarz Pharma

Today Combine leadership in antibody research

& chemistry expertise to better treat severe

diseases

1928 1952 1972 1980s 1990s 2004 2006 2008-2010 Today

Chemical Group Primary Care Pharma Specialty Bio-pharma

Launch of Cimzia®, Vimpat® & Neupro®

(CVN)

1952: UCB discovers Atarax®

U.S. license awarded to Pfizer

1936: UCB enters the United States

1936

2009

3 core medicines for patients with severe diseases

■ Rheumatoid arthritis

■ Psoriatic arthritis (PSA)

■ Ankylosing spondylitis (AS)

■ Axial spondyloarthritis (AxSpA)

■ Crohn’s disease

■ Epilepsy adjunctive therapy

■ Parkinson’s disease

■ Restless legs syndrome

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Unique syringe designed with users for users

A global and diverse workforce

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83%

HIGHLY ENGAGED TEAMS

Creating value for patients

UCB: making lives better everyday

EMPLOYEE by REGION

Why do we need INNOVATION? … 9

Context : where are we? Where do we go?

Needs and constraints

a worldwide market a worldwide economy

but different in each country

Energy, raw material, labor cost, policy of country ( wastes,…), distribution

rate exchange, Level of technology, …

Need and contraints depend on country, …

MANUFACTURING Cost, quality, efficiency, productivity,

Safety, yield, Wastes,

INNOVATION Material Product Process

All these parameters are function of time… A CONTINUOUS CHALLENGE…


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To summarize… the contraints

Keppra : Tablets in US & EU

Sirop in Japan

Source McKinsey Global institut Analysis Solution: manufacturing must be FLEXIBLE, MOBILE, EASY & QUICK to build, SAFE, …at low cost, close to customers…

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To summarize…the solution

Source McKinsey Global institut Analysis Solution: manufacturing must be FLEXIBLE, MOBILE, EASY & QUICK to build, SAFE, …at low cost close to customers…

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Last Innovations which are going to change the world… ? 12

Innovation in a specific domain creates innovation in another ones … or a combination of 2 innovations in ≠ domains can be an innovation in a third domain

1-The interfaces brain-computer, which will allow for one handicapped person to type a text from the monitoring of the electric activity of its brain;

8-The composites of nanostructured carbon, which will make possible the manufacturing of vehicles from strengthened composite carbon fiber and will make them 40 % lighter, more strong and easier to recycle;

10-Energy, a fundamental breakthrough to keep the positive energy associated with the fluctuation in the renewable sources such as the sun and the wind or LIGHT;

2-The portable medical electronics which, by means of a device integrated into clothes or under the skin, allows in real time the follow-up of the heart rate or the stress

7-Microscale 3-D Printing: Inks made from different types of materials, precisely applied, are greatly expanding the kinds of things that can be printed

9-Agile Robots: Computer scientists have created machines that have the balance and agility to walk and run across rough and uneven terrain, making them far more useful in navigating human environments

3-The therapies derived of the micro biome human , which will allow the medicine to handle better serious illnesses and to improve the health thanks to the knowledge of the sequence of the genes and the genomes of the human microorganisms 6-BIGDATA a digital platform,

accessible via an Internet browser or as an iPad app, that stores data from different investigators in a lab, tracks reference materials, logs logistical information such as reagent inventory, and can be used to share experimental protocols and other useful tidbits. “the biggest concern is to get labs to run more efficiently and to be more productive,” The predictive quantitative analysis personalized, which makes possible the construction of models predictive and detailed on people and their behavior and will help, among others, in the urban planning and in the medical diagnosis

4-The therapies with ARN, for a new generation of treatment of the infectious diseases

5- Mobile Collaboration: The smartphone era is finally getting the productivity software it needs; Skype, Lync; Internet,…


The story of 3D Printing… 13

A breakthrough technology : Sometime, it takes time to see all potential applications…. Not too early…

Chuck Hull first came up with the idea in 1983 when he was using UV light to harden tabletop coatings.

But on July 16, 1984 , Alain Le Méhauté, Olivier de Witte and Jean Claude André filed their patent for the stereolithography process.It was three weeks before Chuck Hull filed his own patent for stereolithography.

The application of French inventors were abandoned by the French General Electric Company (now Alcatel-Alsthom) and CILAS (The Laser Consortium).The claimed reason was “for lack of business perspective… And 30 years later…..

LiegeCreative June 2nd 2016

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Some applications using 3D printing…(from µelectronic to big house…) 14

A house built by a 3D printing in california in 1 day...

A piece of motor

What will be the next step?...,

Printing human organs & tissue… why not?

Human skin (Oreal/Organovo) Heart, liver and kidneys? Successful transplantation of an adult kidney into a child.(using 3D Printing) Idea : To review the clinical trials…

3D-printed medications to produce the optimal medication dose as function of age, race and gender… It will be a solution concerning the Personalized medication.

3-D printed-prosthetic hand which identify objects by touch…

Multiple opportunities of the 3D printing in the healthcare industry

My own vision:


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http://www.lepoint.fr/images/2014/02/07/lifehand-2410494-jpg_2072007.JPG

http://www.nanalyze.com/wp-content/uploads/2013/07/Ti64_Part.gif

What will be the laboratory of the future? My own vision 15

How to use all new knowledge and innovative tools ..?

Some challenges: A complex changing world: each week new knowledge

To develop ideas at the right time….( Not too early…)

To gather the right experts at the right time….to achieve the same target

To manage a team composed with a multidisciplinary public and private

researchers/experts over the world with the same objective…

To challenge the ORTHOXOXIE of « experts »…they are afraid of “changing”

Or they tested this technology 10 years ago …

HOW can we do and solve these challenges?


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What could be the laboratory of the future…? 16

With new Communication: Skype, Lync, Web, mobil phone…

Laboratory with an specific expertise

and must develop its expertise continuously With the support of …

Case N°1: Laboratory with a specific EXPERTISE…with the support of a MULTIDISCIPLINARY TEAM, EXPERTS over the WORLD

Laboratory Expert in Analytical method HPLC, UPLC , GC,TEM, XPS, MS/MS,SFC, …

Laboratory Expert in Equipment

Laboratory Expert in automation

Laboratory Expert in Xn.. Technology

Laboratory Expert in PAT

Laboratory Expert in X3 Technology



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What could be the laboratory of the future…? 17

With new Communication: Skype, Lync, Web, mobil phone…

Laboratory composed with GENERALISTS

and must develop pharmaceutical process With the support of …

Case N°2: Laboratory of GENERALIST Researchers…who can communicate with a MULTIDISCIPLINARY TEAM composed with EXPERTS over the WORLD

Laboratory Expert in Analytical method HPLC, UPLC , GC,TEM, XPS, MS/MS,SFC, …

Laboratory: Experts in Chemical Engineering, Equipment

Laboratory: Experts in Chemistry: reaction: New solvent, catalysts, New way of activation, Formulation, ….

Laboratory Expert in Xn.. Technology

Laboratory Expert in PAT



Laboratory: Experts in Biology: Cell culture Protein purification, Formulation, …


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Innovation :

Ideas about Sciences / Resources / Budget Innovation at UCB : The process…

Ideas become a project with Resources / Budget


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Ideas become a project like other other Projects

Initiation Definition Execution Closure Ideas

Justification Options Feasibility Prioritisation

Studies Chart Planning

Coordination Monitoring Performance

Documentation Verification

Ideas Request

Approval

Approval

Baseline

Implementation

Verification /tests

WHAT & WHY

HOW What Who When

HOW it is done

HOW good It was

Go/No-go decisions

Controlling

Steering Committee

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Application on LEGOMEDIC Project 20

Acronym, WHAT are the objectives , WHAT are the partners / organization, ….and first results…

LEs

Générations

Outils

Milli/micro

Equipements pour le

Développement et

Industrialisation de

Composés

.Chimiques/Biologiques

The LEap Generation of

tOols Milli/micro

Equipemnt for the

Development and

Industrialization of Chemical & Biological

Compounds

. Project has started in 2013….


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21 Chemical and/or Biological industrial process are very similar …

Input : Raw materials

Reactions / Fermentations/Cell culture

Purification / UPS/DWS

“Pre Formulation” Crystallization/Precipitation

Output : Final products

Che

mic

al o

r bio

logi

cal

Proc

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22 Whatever the chemical or biological process, what are the challenges? How to solve them ?

FLEXIBLE Chemical Process : Increase the productivity Reduction of number steps , wastes and energy consumption

■ Reactions: New Raw materials, New solvents, New catalysts, new physical activation (MW, US, Photochemistry, …)

■ New solvents for purification,

■ New solvents for crystallization New technologies

■ New Equipment for CONTINUOUS Reaction, crystallization, Purification.

■ Software: to model, to simulate, to optimize, Statistic tools

■ To control : PAT, …

FLEXIBLE Biological Process Increase the productivity Reduction of number steps , wastes . and energy consumption . Cell culture or Fermentation: New

media, new nutrients, new line cell. New biomolecules to capture the

desired biomolecules for purification. New agents of Precipitation ??

New technologies

New Equipment for CONTINUOUS fermentation and Purification

Software: to model, to simulate, to optimize, Statistic tools

To control : PAT,…


TOOL BOX To have a Holostic approach of the process

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LEGOMEDIC Project : Concept… plug and play

Classical Legos

« Specific » Legos As function of needs

Manufacturing Units : Skid Reactions/Purification/Solid

Holistic Optimization

Manufacturing Units : Skid Reactions/Purification/Solid Design

Number of Skids A function of market


LEGOMEDIC project : Objectives…

To create a technical platform to develop a TOOL BOX:

• For R &D laboratory and industrial plant (with PAT and automation)

• For the development and manufacturing of NEW CHEMICAL and

BIOLOGICAL API, by respecting all constraints (Quality, Safety, Green

chemistry, …) •

To develop innovative chemical and biological processes • CONTINUOUS Chemical Process : from raw material to API

• CONTINUOUS Biological Process: Continuous protein purification


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In 2013 , what was the situation concerning existing equipment for continuous process…at lab scale and

industrial scale Chemical Process

Laboratory Industrial

Purification

Reactions

Crystallization

Reactions < 200 steps ..

Purification

Crystallization

Fermentation 1 known industrial case : DSM: Perfusion Bioprocess

Purification Under studying

Fermentation Perfusion: Some existing equipment

Purification Under studying

Biological Process Laboratory Industrial

≅60%

< 20% < 10%

< 20% < 20%


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LEGOMEDIC : Flexibility of chemical & biological production, To adapt number of SKIDS to the market:

Mono or Di Nitration

Hydrogenation


LEGOMEDIC : FLEXIBILITY, AGILITY in a quick time…. Scale up or Number up ?

Number up for production Time: 3 - 6 months without risk

At lab scale: optimization of all operating conditions

Scale up for production Time: 2 to 3 years

with risks

Low volume High T & P: safety High Productivity & Yield

Reduction: wastes & Energy consumption Reduction OPEX & CAPEX by 2…


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Number of Skids A function of market

Protein Purification : the challenges BATCH or CONTINUOUS?

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X1 Antibody Batch process (16 Steps) Complex Purification Process Capture Purification Polishing Several steps are the same UF (4), Centrifugation (2) HPLC(5),Dilution, Extraction, Reduction…) with large volume High dilution…

Objective: Batch: 15-20 Steps . Continuous < 10 steps

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Material type

Research center

29 LEGOMEDIC: Team composition…Different experts working

in different Universities and private companies over Europe with PhD students, PostDocs …

Suppliers of Equipment

Micro/Mili “tools”, Automation µ sensors,

to build the SKID

Biological process R&D:

Purification : 5 ≠ Technologies

With 6 teams in different Universities & countries

UCB: Project manager

Chemistry Process R&D

Reactions-Purification-Solid Design On a full continuous process

With 6 teams in different Universities & countries


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LEGOMEDIC: 3 years later… 30

Results… For confidentiality reason, No result can be presented… CHEMICAL process: 2 patents in Nov 2015 1 patent must be submitted in Sept 2016

BIOLOGICAL Process 1 patent must be submitted end of May 2016 2 or 3 must be submitted for end of 2016

A start-up is under creation…

It is a great success…. Thanks to the partners E Lecomte Norrant LiegeCreative June 2nd 2016

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From laboratory to the Manufacturing of the future… Flexible(LEGO), Mobile, …

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This backbone facility supplies utilities like electricity, heat, cooling water and service gases

Batch process : 4 days Continuous process? Neat reaction …

Step 1: Step 3: Step 2: Step n:


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Docking station

+ + +

Example of a full mobile autonomous manufacturing equipment…

To be used in special events ( in case of wars, tsunami, … no electricity)

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Example : from MIT (March 2016)

A mobile manufacturing plant ( size of a refrigerator) to manufacture different drugs such as lidocaïne, fluoxetine, diazepam and diphenhydramine…

It is possible to manufacture 1000 doses of a drug in 24 hours..

Holistic approach of the process: Close interdependence between chemical or biological steps which close communication between chemical and biological experts To reach an optimum on global process

Quality, safety, Productivity, with the respect of green chemistry and with a limited financial risks LEGOMEDIC is the POC that the virtual laboratory could be a new way of working with an excellent efficiency to develop new process: It is a great success…

New TOOLS

New MEDIA

New ACTIVATION CHEMICAL

BIOLOGICAL REACTION

Conclusion: Chemistry/Biological Process A multidisciplinary, international Team…


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From the present to the close FUTURE.

A flexible plant built from modular skid

Ref. = DSM

To develop a full tool box to work continuously Reactor, Bioreactor

Purification

Design of solid / Formulation for antibody

PAT

Softwares, big data...

Plug and play

To avoid SEVESO

manufacturing plant…


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From the present to the FUTURE… 35

If you want to know the FUTURE , dream it and create it ! For a better chemistry for a better life… Due to the quick evolution of technology and innovation, it is difficult to predict the manufacturing plant in 40 years. But the future starts now …


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Questions? 36


Thanks To the LEGOMEDIC ‘s partners Over Europe

12 masterstudents, 7 PhD, 5 PostDoc and Public Resaerchers from Belgium, France, UK, …

Next step: To increase my network over the world…

Thank You for your attention!

Questions? 37


Thanks You for your attention!

E Lecomte Norrant FC2GChem May 9th – 13th 2016

Univ Graz Austria

Kinetic data..

Some examples concerning the use of microfluidic..

P1 P2

0 °C

BPR

Tubing section : 0,81 mm

20°C

0.5mL

25 mL

5M, 5 mL.min-1 5M, 5 mL.min-1

N Me2SO4

Flow Chem: Scale : 1 mole Injection time : 40min Reactor Vol : 0.5mL Productivity : 7.4 kg / day either 1480 kg/L/day

Batch Mode : Max Scale : 1 mole Addition time : 12h Reactor vol : 2L Productivity : 170g / day either 85 g/L/day

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Highly exothermic reactions IONIC liquids synthesis

REf : M PUCHEAULT 2010

P1 P2

P3

2 mL/min 2 mL/min

0,5 mL 8 sec 4 mL/min

13 mL 1min40

5 °C

1,3M (cyclo/hex : 92/8) 0,5M

0,27M

Li

Br

OH

O

Flow chem : Scale: 0.2 mole Injection time : 3h 20 min Reactor volume : 0.5mL Productivity : 325g / jour Temperature : 5°C Yield: 65% Productivity : 650 kg/L/day Purity: 85%

Batch mode: Max scale: 0.2 mole Addition time : 8h Reactor volume : 1L Productivity : 45g / day Temperature : -78°C Yield: 50% Productivity : 45g/L/day Purity: 72%

Other example: O-lithiation/trapping

Ref : M PUCHEAULT 2010

A3P Nov 17th 2011 SPA E

NO

RR

ANT

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Ref : M.I.T.

Purification Segmented flow tubular reactor Liquid /liquid plug flow reactor : perfect segmentation

PURIFICATION STEP A Liquid/liquid extraction: Segmented flow tubular reactor

100 µm

Ref : IMMainz Generation of small droplets in a micromixer

FORMULATION

25/60 micromixer

Dyed water / silicon oil 100 µm

100 µm

100 µm

100 200 300 400 500 600 0

20

40

60

80

Dro

plet

siz

e [µ

m]

Volume flow [ml/h]

60µm

40µm

20µm

Ref IMMAINZ

VARIATION OF DROPLET SIZE BY INCREASE OF VOLUME FLOW

Tahseen Razzaq and C. Oliver Kappe Chem. Asian J. 2010, 5, 1274 – 1289

Continuous Flow Organic Synthesis under High-Temperature/Pressure conditions

New continuous process using micro fluidic, automatic system, in safe conditions under analytical control (PAT) for

Reaction

Purification

Solid design

In NEW OPERATING CONDITIONS Minimize mixture volume with “EXTREME” operating conditions:

• Pressure P = 0 bar up to 500 bars • Temperature: T= -80 °C up to 300°C • Residence time : τs = s up to hours • Material : Stainless steel, Glass, Teflon, hastelloy, …

Micro Reactor Technology /Process Intensification : MANY ADVANTAGES

CRITERIA: Reaction Classification & Microreactor Technology Advantages ( Scale From Lonza Ref D LABERGE 2005 lonza)

Type D Reactions: We do not know …how to do…

21%

50%

6%

23%

Potential : 50% of reactions is waiting for NEW IDEAS

What are the potential reactions?

Du laboratoire à l'usine du futur : gestion de l'innovation dans l’industrie pharmaceutique par...

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