Ways Forward – Vaccine Manufacturing Tomorrow

Jerome Dalin
Senior Consultant, Core Modalities, Europe, Bioprocessing Strategy
Xiaolong Sun
Senior Manager, Pharma Regulatory Advocacy & Consultancy Service APAC
Josephine Cheng
Senior Consultant, Core Modalities, APAC, Bioprocessing Strategy
Webinar November 9, 2021
Ways forward –
Vaccine Manufacturing
Tomorrow

2
The Life Science business of
Merck KGaA, Darmstadt, Germany
operates as MilliporeSigma
in the U.S. and Canada.
Ways Forward - Vaccine manufacturing tomorrow | Nov. 2021

AGENDA
Introduction
about Vaccine
manufacturing
1
2
3
The Trends
- - Manufacturing
platforms
- - Industry 4.0
Next steps and
impacts
4
Our Capabilities
to Support
Vaccine
3

Introduction Vaccine today
Though COVID-19 has remarkable records, there are remaining
actions needed to strengthen the vaccine ecosystem
4
Int’ Organizations
WHO/GAVI
Manufacturers
Caregivers
Govt.
Regulatory
Agencies
Foundations
1st EAU in
362 Days
11B COVID-
Doses (2021)
vs 5.5B (2019)
1st COVAX
shipment
in 80 days
after HIC
Sustainable
Immunization
programs
Reduce
morbidity/
mortality
No. of
vaccines
indications
Global
Pandemic
Preparedness
Global
Equitable
Access
Ensure supply
meets
demand
Skilled
workforce
New models
increases mfg.
capacity
Digital
Technologies
/ innovations
Trust &
confidence in
community
Maintain
Prioritization/
Investment
Ecosystem
Source:Vaccine Ecosystem consensus statement, The Economists, May 2021
High Quality
Standards

01
Introduction
about vaccine
manufacturing
5 Ways Forward - Vaccine manufacturing tomorrow | Nov. 2021

Evolution of vaccine processing
Industry 4.0
Agile vaccine
manufacturing
COVID pandemic
acceleration
The current COVID pandemic and the Industry 4.0 acceleration
have dramatically highlighted the desire and need to have
concrete solutions for agile vaccine manufacturing
New way of
working

Vaccine Factory Transformation
1
• Large floor space and
cleanrooms
• Complex piping
• Extensive preparation
7
1990S Legacy
Now : New facility
generation
3
4
Factory of the
future
Lonza Cocoon® Platform
Univercells NevoLine™ Platform
iCONTM ready PODS
Reduce floor plant for non
productive activities
Smaller clean rooms
Simple infrastructure
Supply on demand
Open rooms
Lower room classification
Multiproduct
Closed & smaller processes
Ultra compact & Full
equipment orchestration
Modular & Flexible (easy
scale-up)
Fully integrated (process/QC)
Fully closed
2
2010S Pre
designed facilities

Scalability
Need to be able to produce huge amount of
doses in a short time
Global vaccine manufacturing capacity may
not be sufficient for COVID19
Time
The typical vaccine paradigm doesn’t allow
adequate response to tackle outbreaks
Cost
Vaccine development & licensure requires
>$500 million
No guaranteed long-term market
Major Challenges in Vaccine manufacturing with Outbreak & Pandemic
A Paradigm Shift with Pandemics
8
Time Compression
From 10+ to 1-3 years (From
PD to Commercialization)
Platform technology
Focus on mRNA, Viral Vectors,
VLP etc.
Technology
innovation
Single-Use (Final Fill, full SU
platforms etc.), Yield
improvements…

What makes “factory of the future” difficult to design for Vaccines?
9
DNA
vaccine
Traditional vaccine
Conjugated
vaccine
Viral vector
vaccine
Virus-like
particles
Modern to cutting edge vaccine
Live
attenuated
virus
Inactivated
virus
RNA
vaccine
« One bug – one drug » « One platform – multiple vaccines»
Toxoid
Whole
bacteria
Recombinant
protein
Biosafety
• Fully closed processing to protect
✓ Operators
✓ the product when sterile filtration is not possible (Live
Virus Vaccine)

10
Virus
Fragmentation
Media &
Inoculation
preparation
Fermentation &
virus Infection
Clarification
Virus
inactivation
Filtration
Concentration
Centrifugation
Nucleic acid
removal
Clarification
Virus inactivation Concentration Sterile filtration
Final Fill
Fertilized Eggs
& Virus Infection
Clarification Virus
inactivation Pre-
Filtration
Concentration
Centrifugation
Virus
Fragmentation
Clarification
Virus inactivation
Concentration
Sterile filtration Final Fill
Flu Vaccine process comparison
Cell based
Egg based
VS

11
Conjugated polysaccharides vaccine
Neisseria meningitidis -surface blebbing.

- Multiple modalities
- Multiple Biologic agents
- Biosafety : Cross
contamination
- Products & operators
protection
- Could require full process
sterility
- Conservative mindset
(Historical treatment)
Evolutive factory for vaccine : easiness for implementation
12
Implementation
Vaccine
Mab
- One modality
- Easier Biosafety
management
- Product protection
- Innovative mindset
Vaccine vs
Mab
comparison

Making flexible factories for vaccine is possible today!
13
• Process simplification : One process for one disease vs Manufacturing Platforms
• Smaller equipment footprint => smaller facilities
• New facility type & new ways of working : Automation, Modular, BallRoom, digital twin
• Single-use products
Development of new technologies as Digitalization, equipment modernization and
progress in bioscience allow the transformation of vaccine biomanufacturing :
Advantages of Single-use technologies
- Reduce Capital
- Reduces cross contamination risk (closed processing)
- Ease to use (plug and play)
- Reducing cleaning costs
- Faster production
- Flexibility to scale or process

Making flexible factories for vaccine is possible today!
14
• Process yield improvements : Continuous processing / Process Intensification etc.
• More collaborations between big manufacturing players and universities, small biotechs etc.
(ie. AZ with Oxford University, Pfizer & BioNtech etc.)
• Carbon footprint care / Focus
CO2
Example of recombinant process

02
The trends (1/2)
15
Manufacturing platforms

Templates vs Traditional vaccines
Supports
bioprocessing
standardization
1
Reduce process
development
time and cost
2
3
4
Reduce
significant
manufacturing
changes
Ease of
regulatory
approval

Process comparison between classical template vs Platform
17
mRNA Platform
In vitro
Transcription
Chromatography UF/DF
Linear DNA mRNA
pDNA
Purify
Make
mRNA
LNP drug
product
Encapsulation Sterile Filtration &
Fill and Finish
mRNA
UF/DF &
Final formulation
Formulate
1 2
3
VS
Inactivated
process template
Biological Manufacturing Enzymatic Reaction
Make
1
Purify 2
Formulate
3
Chromatography
1-3 steps
UF/DF
UF/DF Inactivation Clarification
Formulation Sterile Filtration and Final Fill
Cell Amplification
Media
Preparation
Bioreactor and
Cell Growth
Nucleic Acid
Digestion

mRNA technology
Advantages
1 RNA therapeutics are safer
than DNA therapeutics
(RNA does not integrate
into the Genome)
RNA is not infectious
RNA is produced using a
cell-free enzymatic
transcription reaction or
chemical synthesis
2 Production of RNA-
based vaccines is
faster compared to
production of
traditional vaccines
Good scalability
3
Producing RNA
vaccines is less
expensive than
producing the full
antigen protein
4
For any outbreak
RNA vaccines are
more flexible, any
desired RNA for any
desired protein of
interest can be
prepared in short time
for each individual
patient (personalized
medicine)
Safety
Time
COst
Flexibility
18

mRNA technology
Challenges
1 Single stranded
Highly negatively charged
Rapid degradation of RNA
caused by endonucleases
Cold-chain
2 Exogenous mRNA is
immunostimulatory, as it is
recognized by a variety of
innate immune receptors
RNA instability
Immune modulation
19

02
The trends (2/2)
20
Industry 4.0

Source: Sanofi - EVF presentation – French Bioproduction Tour - 2021
A new way to design vaccine manufacturing facilities

Hybrid Modular Biologics Platform
22
A flexible and rapidly
deployable facility platform
based on a process
consensus design
philosophy.
iCON™ can be adapted to
biomanufacturing
production needs from 20L
up to multiples of 2000L
scale.
This concept allows :
• Biosafety containment between each module
• Multimodal biomanufacturing into the different modules (Different
vaccine templates / Mab process / Viral and gene therapy…)
• Flexibility to increase capacity by module addition
Source : IPS and CRB website
Process
Equipments
Modules
Facility

BallRoom concept
23
Source : SU Bioprocess Platform for Veterinary Vaccine & Biopharmaceutical
pilot scale production- Francis Verhoeye – Zoetis - June 15th 2020
Concept and requirements :
• Big room with different unit operations which can be moved according to the process needs/template
• Mobile equipment's required (to limit as much as possible) – Keep “3-meter rule” to minimize tubing length and volumes
• Full closed processing required to move from one campaign to another one or if handling multiple processes in parallel
• From BSL1 to BSL3
• Ideal for CDMO activities – Flexibility to jump from one product to another one.
• Ball room with docking
stations – Class C
• Central area for buffer and
media – Class D
Source :https://ispe.org/pharmaceutical-engineering/november-
december-2020/biopharma-facility-design-lessons-learned-dance

Process Automation / Robotization
25
Environmental
Monitoring
Water
Sampling
Product
Sampling
1000L
Bioreactor
Sample
transfer
Sub Aliquot
Insertion of
Sample for
Analysis
Kitting of
materials
Movement of
materials
Source : ISPE / Biopharma Facility Design: Lessons Learned on the Dance Floor / Nov Dec 2020
All tasks done :
- with operators in
one shift (8:00AM to
5:30PM)
- Overnight with
automation and
robotization (no
manual operations)
Manufacturing Room
Robots/Cobots can now support your manufacturing steps
Example of automation strategy for USP

Successful proof of concept project.
Next step for GSK : Replicate the
digital twin concept on an industrial
scale for its vaccine development
and manufacturing platforms.
Partnership with Siemens and Atos
to pilot a digital twin for their
vaccine manufacturing process that
modeled and controlled the adjuvant
particle manufacturing process
Digital Twin
26
Source : https://www.pharmtech.com/view/gsk-pilots-digital-
twin-for-vaccine-manufacturing
Example of GSK Vaccines
We developed Bio4C™ software for
process orchestration and automation
part of BioContinuum® Platform

Energy
CO2
Water
Reducing
environmental
footprint
On-going projects
EVF project for VACCINES
(France & Singapore)
Chemicals
Waste
CO2
Source : Sanofi Webpage
Existing Factory 4.0
Example of Sanofi for mAb
mAb facility – Former Genzyme plant
• Facility size reduction
• Number of unit operations
• Shorter cleaning circuits
• Time between two
campaigns
Major improvements
27

mRNA Conceptual Facility Design
Case study from KSA
Revamping existing facility to make new Conceptual Facility Design for the first
mRNA CDMO facility in KSA as part of a multi-modality CDMO
3D High level overview of
Warehouse + F&F Building
Warehouse + Fill & Finish building Deliverables
• Process flow diagrams
• Capacity: Batchs/yr & Doses/yr
• Equipment list
• Facility layouts with process,
waste, people, materials flow,
room classification, pressure
cascade
• APEX, OPEX
• Review and assessment of
regulatory compliance
• Optimization proposals
• 3D layouts and plans
pDNA and mRNA Facility Layout
Area
Fill & Finish / Cleaning area
mRNA production area
M/B preparation area
pDNA production area
28

04
Next steps &
Impacts

Schools, universities and learning
centers will have to adapt their offer to
train the next generation of vaccine
biomanufacturers of Industry 4.0
Be prepared!
People profile
Today :
People in charge of Vaccine manufacturing are Biologists working with
automation engineer
Tomorrow :
People in charge of Vaccine manufacturing will be “BioAutomation” engineer
30

Sourcing / Supply of raw materials
31
Covid 19 impact:
Most of pharmaceutical suppliers have been dramatically impacted by the pandemic
Tomorrow :
To better secure the supply chain different options could be considered :
- Dual sourcing could become the normality but requires additional investments in time,
resources etc. to duplicate validations/qualifications
- Different stock management
- Collaboration with suppliers
• Forecast accuracy
• Stock management
• Pandemic preparedness program
• Prioritization and focus on critical materials…

!
Closed processing
32
Today :
One of the major gap today is closed processing for some specific
technologies which are difficult to close.
Chromatography is one of the most difficult step to close especially if
sterility is required (ie. Live virus vaccine):
- Column sterilization
- Resin stability with gamma irradiation
Tomorrow :
Ideally the membranes could replace chromatography columns with resin
- Self contained
- Sterilizable (Y/N?)
- Implementation possible in single-use assemblies if gamma stable
(or autoclavable?)
Fully closed
Vs
Functionally closed

Robotics
33
▪ Reproducibility and process
robustness improvements
▪ Development and process
time Reduction
▪ Process Platform
Towards the full automation with Robots, Cobots and AI?

04
CAPABILITIES
TO SUPPORT
VACCINE

Vaccines, empowered
“You want to scale and deliver your vaccine to the
world quickly. Our collaborative global vaccine
capabilities will take your innovation from
discovery to full-scale GMP-manufacturing
efficiently, safely, and cost-effectively.
Discover how expertise— empowered by
collaboration—can refine mRNA approaches or
overcome manufacturing challenges in more
traditional modalities.
Vaccines,
empowered

Our LS Bioprocessing vaccine segment
Accelerating the development & manufacturing of vaccines
Advancing manufacturing
templates
 Life science technologies exploration
& POCs
 Collaboration with Institutes &
private organizations to translate
processes to GMP ready
Industry collaboration &
projects
 New technologies development
 Process development & optimization
 Tech transfers support
Vaccine focus organizations
 Industry/Government groups presence,
partnerships & trainings
 Publications
 Dedicated application notes & web
microspace
 Voice of the industry
36
Understanding the needs of the vaccine industry and
applying a holistic approach

Advancing vaccine manufacturing
Capabilities across the chain to accelerate the journey
2 Scale up
Mobius® Single-Use
assemblies or multi-use
Equipments
1 Process
development
Support & services
Incl. collaboration with
3rd parties
3 Testing &
Services
Bioreliance® testing
,Validation & CDMO,
Regulatory
consultancy services
4 Facility design
& building support
incl. partners
37

38
Quality Management
System Establishment
Evolution of vaccine processing to accelerate innovation / 09Nov2021

Quality Manual
Quality Systems
(Standard
Master
Procedures)
Production
Governing
Procedures
Quality
Control
Master
Procedures
Validation
Program
Procedures
and Plans
Engineering
and
Maintenance
Governing
Procedures
Data
Integrity
Master
Procedures
Establish Quality Management System
Project Execution Overview
 STAGE 1
 STAGE 2
 STAGE 3
 STAGE 4
 STAGE 5
 STAGE 6
 STAGE 7
39

STAGE 1 – Quality Manual
Quality Manual will be developed by the Consultancy Principal Consultant (GMP Compliance Expert)
Quality Manual built upon ICH Q10 Pharmaceutical Quality System, will include the Quality Policy and
outline of the Quality Systems that will be defined in detail in the Master Documents to be developed
during the other project stages
40
Quality Manual
Quality Systems
(Standard
Master
Procedures)
Production
Governing
Procedures
Quality
Control
Master
Procedures
Validation
Program
Procedures
and Plans
Engineering
and
Maintenance
Governing
Procedures
Data
Integrity
Master
Procedures
 STAGE 1
 STAGE 2
 STAGE 3
 STAGE 4
 STAGE 5
 STAGE 6
 STAGE 7

STAGE 2 – Quality Systems
The Standard Master Procedures will define the Quality Systems based on the organization and
functions of site.
41
Quality Manual
Quality Systems
(Standard
Master
Procedures)
Production
Governing
Procedures
Quality
Control
Master
Procedures
Validation
Program
Procedures
and Plans
Engineering
and
Maintenance
Governing
Procedures
Data
Integrity
Master
Procedures
 STAGE 1
 STAGE 2
 STAGE 3
 STAGE 4
 STAGE 5
 STAGE 6
 STAGE 7

STAGE 3 – Production Governing Procedures
The Production Governing Procedures will define the Production requirements and controls based on the
role of the site, e.g. MAH or CDMO.
42
Quality Manual
Quality Systems
(Standard
Master
Procedures)
Production
Governing
Procedures
Quality
Control
Master
Procedures
Validation
Program
Procedures
and Plans
Engineering
and
Maintenance
Governing
Procedures
Data
Integrity
Master
Procedures
 STAGE 1
 STAGE 2
 STAGE 3
 STAGE 4
 STAGE 5
 STAGE 6
 STAGE 7

STAGE 4 – Quality Control Master Procedures
The Quality Control Master Procedures will define the Quality Control requirements and controls, e.g.
specifications, analytical methods, samples management, environment monitoring.
43
Quality Manual
Quality Systems
(Standard
Master
Procedures)
Production
Governing
Procedures
Quality
Control
Master
Procedures
Validation
Program
Procedures
and Plans
Engineering
and
Maintenance
Governing
Procedures
Data
Integrity
Master
Procedures
 STAGE 1
 STAGE 2
 STAGE 3
 STAGE 4
 STAGE 5
 STAGE 6
 STAGE 7

STAGE 5 – Validation Program Procedures and Plans
The Validation Program Procedures and Plans will define the Validation Program Procedures and Plans
requirements, e.g. validation policy, specific validation standards (facility, utility, equipment, cleaning,
process, shipping, etc.)
44
Quality Manual
Quality Systems
(Standard
Master
Procedures)
Production
Governing
Procedures
Quality
Control
Master
Procedures
Validation
Program
Procedures
and Plans
Engineering
and
Maintenance
Governing
Procedures
Data
Integrity
Master
Procedures
 STAGE 1
 STAGE 2
 STAGE 3
 STAGE 4
 STAGE 5
 STAGE 6
 STAGE 7

STAGE 6 – Engineering and Maintenance Governing Procedures
The Engineering and Maintenance Governing Procedures will define the Engineering and Maintenance
requirements, e.g. preventative maintenance, calibration, spare parts management, etc.
45
Quality Manual
Quality Systems
(Standard
Master
Procedures)
Production
Governing
Procedures
Quality
Control
Master
Procedures
Validation
Program
Procedures
and Plans
Engineering
and
Maintenance
Governing
Procedures
Data
Integrity
Master
Procedures
 STAGE 1
 STAGE 2
 STAGE 3
 STAGE 4
 STAGE 5
 STAGE 6
 STAGE 7

STAGE 7 – Data Integrity Master Procedures
The Data Integrity Master Procedures will define the Computer System Validation and Data Integrity
requirements, e.g. data management policy, CSV policy, account management, audit trail management,
business continuity, disaster recovery, ERES management, etc.
46
Quality Manual
Quality Systems
(Standard
Master
Procedures)
Production
Governing
Procedures
Quality
Control
Master
Procedures
Validation
Program
Procedures
and Plans
Engineering
and
Maintenance
Governing
Procedures
Data
Integrity
Master
Procedures
 STAGE 1
 STAGE 2
 STAGE 3
 STAGE 4
 STAGE 5
 STAGE 6
 STAGE 7

47
Qualification and Validation
Reference
QRM
Third Party
Services
Knowledge
Management
Change
control
Deviation
Management
……
Data Integrity
Support
Activity
ICH Q8
ICH Q9
ICH Q10
ICH Q11
EudraLex,
Volume 4,
Part I/Part II
EU GMP
Annex 11
EudraLex,
Volume 4,
Part I Chapter
3,5
EMA Guideline
on process
validation for
finished
products
PQS
Qualification and Validation
Procedure
VMP
VP
Organizing and
Planning for
Qualification and
Validation
URS DQ
FAT
SAT
IQ OQ PQ
Re-qualification
Equipment,
Facilities,
Utilities,
Systems
Process
CSV AV CV
PV
Validation of
Packaging
Verification of
Transportation
Leverage
FS
DS
Life Cycle

Summary
1. Covid-19 and bioprocessing 4.0 accelerates the
development of vaccine Facility of the Future,
characterized by a more intensified, continuous,
predictive, and autonomous operation.
2. Vaccine manufacturing is moving into new
generation incorporating the following concepts:
a fully single-use process, closed processing,
modular facilities, and platform manufacturing.
3. Laveraging solution providers’ expertise
including QMS system establishment, regulatory
consulting, Testing services, CDMO services, and
quality products with regulatory support dossiers,
are key to reach win-win situation and speed to
market.

Merck, Millipore, SAFC, BioReliance , BioContinuum and the vibrant M, are trademarks of Merck KGaA, Darmstadt, Germany or its affiliates. All other trademarks are the property of their
respective owners. Detailed information on trademarks is available via publicly accessible resources.
© 2021 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.
Thank you very much for listening!
For more information about Vaccine Production: please visit SigmaAldrich.com/Vaccines

Ways Forward – Vaccine Manufacturing Tomorrow

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