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How Merck Continues to Explore
Speeding Vaccine Development
Timelines
Vaccine Technology Summit
March 20 – 21 2023
Kay Hunsberger
Executive Director
Merck & Co., Inc., Kenilworth, NJ, USA.

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Agenda
 Approach to Rapid Response
 Product and Process Development
 Analytics
 Manufacturing and Facilities
 Regulatory Approaches
 Case Study – Ebola Zaire
 Case Study – COVID
 Case Study – Ebola Sudan
 Lessons Learned and Future Opportunities

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Typical Timeline for Vaccine Development
•8 to 12 Years
•Standard timeline to develop a vaccine.
2028+
2020
This timeline is not acceptable for an epidemic or pandemic!

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Rapid Product and Process Development
Platform Approaches
• Companies leverage their existing platform processes or
establishing new platforms in order to gain speed
• Strong technical knowledge of the platform – process and
analytical
• Leverage existing pre-clinical toxicology studies
• Existing materials/consumables allows work to begin immediately
• Use of existing manufacturing platforms allows for quick
transitions to GMP manufacturing
• Single Use technologies and standardized unit operations allows
for rapid transfer to commercial facility
• Implement continuous manufacturing processes to addresses
product demand

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Transition toward Real Time Release
Incoming QA/
Manufacturing
Sampling
Chain of
Custody
QC Testing
Electronic
Systems
Data for
Decision
Predictive Product
Attribute Control
•Main
F
•Block
•Xv
•TC-Xv
•pCO2
•Gluc
•Lac
•Gln
•Glu
•NH4
+
•Osmo
•Temp
•DO
•pH
•AA
2
F
•AA
3
F
Acidic
Basic
Basic1
HMW
Oxidation
•IEX
•AA
1
F
Time
Conventional QC/QA Future: Real Time Quality Release
Immediate
verification of
Product/ Process
Attributes
Shop Floor
Insitu QC
testing
Data for
Decision
Electronic
Systems

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End to End Analytics for Multi-Modal Vaccines
• Live attenuated viruses
• Genetically modified viruses
• Virus-like particles (VLP)
• Ps-conjugates
• mRNA vaccines Attribute Analytical Methods
Identity Sanger Sequencing, Immuno-plaque
Potency Plaque, qPCR, reporter gene assay, cell based ELISA
Residuals PCR, qPCR, spectroscopy
Safety Sterility, Endotoxin, Mycoplasma, Adventitious agents
Ps-CRM conjugate
Ebola vaccine
rVSV-ZEBOV
• Innovation in vaccine clinical assays
• Business impact:
• Faster turn-around time
• Higher throughput
• Lower test cost
Gardasil (VLP)
Live viruses

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Manufacturing
• Self supporting manufacturing facility – media/buffer manufacture, sterile supply
• Minimizes potential supply chain concerns
• Platform processes
• Ability to manufacture different platforms (mRNA, viral vectors and bacterial vectors)
• Provides ability to purchase and stock raw materials (powder medias and salts) and consumables
• Maintain key process equipment
• Staff trained in platform process operations which allows for rapid response
• Risk based approach to manufacturing schedule – overlapping batches Master Seed and Drug Substance
• Clinical Facility
• Flexible facility – able to do non-GMP and GMP work
 Development work can continue while manufacturing clinical materials
• Combination of Single Use and Stainless Steel to support multiple platforms
• Open floor concept to support multiple unit operations

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Adaptive Process
Control via PAT Tools
and Models
Synchronized supply chain
Automated Continuous Processing
Flexible Multi-Product Facility
Modular/Podular Concept
Expansion via Scale out
Flexible Manufacturing Facilities of the Future
Single Use Closed Processing
Molded
parts

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Regulatory Approaches
• Many countries provide alternatives regulatory approaches to diagnose, treat or prevent a life-threatening
disease
• Use of Animal Rule, Utilization of prior research work, Intermediate clinical endpoints
• Enhanced interactions and early dialogue with the agencies throughout development to rapidly get product to
the patient.
• Providing key clinical data to support product safety to proceed rapidly into Phase 2 and 3 trials.
For Ebola:
• From 2015-2019, there were 23 informal and formal regulatory CMC interactions.
• First filed EUAL - May 30, 2016 however doses were provided under a Pre-License Patient Access clinical
protocol

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ERVEBO® Case Study

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CASE STUDY: Ebola Zaire Vaccine
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rVSVΔG-ZEBOV-GP, live attenuated
This vaccine is a live, attenuated, recombinant vesicular stomatitis virus (rVSV)-based,
chimeric-vector vaccine, for which the VSV envelope protein was deleted and replaced (ΔG) by
inserting the envelope glycoprotein (GP) of Zaire ebolavirus (ZEBOV). There is no live Zaire
ebolavirus in the vaccine.

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Merck’s Approach to Address Potential Vaccine Needs and Vaccine
Availability
Collaborate with current dose owners and stakeholders to align on best use of existing doses of
vaccine (~150 – 170K)
•Intended for expanded ring vaccination trials, new or expanded trials for at-risk US-based and ex-US populations, etc.
CLINICAL
SUPPLY
Ramp up Merck Clinical manufacturing capabilities to produce additional doses that could be deployed in the
case of expanded or new outbreak
•Ethical obligation to ensure vaccine available
•Utilize the WHO Emergency Use Authorization process (new process/first time application) however we ultimately used PLPA process to release
doses
SCALE UP
Move monovalent frozen product forward for licensure as efficiently as possible
• Produce required safety database and demonstrate evidence of clinical benefit.
• Prepare commercial manufacturing facility and execute on process transfer and PPQ activities.
COMMERCIALIZE

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Merck’s Vaccine Milestones and Accelerated Development
Timeline

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Clinical Manufacture - Approach to Accelerate
Development Focus
-Scale-up to 400 Roller Bottle scale (~4.5X increase from clinical batch size)
Approach
-Leverage prior knowledge of cell line and roller bottle process operations
Parameters
-Multiplicity of Infection
-Day of Infection
-Harvest Time
-Depth Filtration
-Enzyme Reaction
-TFF
Literature, CMO
Data Review
and Merck
Expertise
Process
Development
Kick-Off
[Jun2015]
Scale – Up
experiments
[Jun–Oct2015]
Produced Drug Substance sufficient to make >750k doses
DS-DP
Manufacture
[Oct-Dec 2015-
Jan -Feb 2016]

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Ebola Zaire Vaccine Drug Substance Process
Dispense and
storage
Harvest
Clarification
Filtration
Nuclease
Digestion and
Enzyme
Treatment Ultrafiltration
Cell Seeding and
Passage
Cell Expansion
Infection
Single Use with a fully closed downstream process

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Ebola Zaire Drug Product Profile
 Single dose and 10 dose image were used in clinical
trials
 Provides flexibility on treatment approaches
 Final commercial image is single dose
 Stored at -70C
 Short term storage 2-8C for 2 weeks and 25C for 4
hrs. for use in the field

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Approach to Analytical Comparability
1. Contract Manufacturing
• Initial Clinical Dose experience
2. Biologics Pilot Plant
• Scale-up to commercial scale
• Emergency Use/Clinical dose
Manufacture
3. Commercial
• Process characterization
• Transfer from pilot plant to
commercial site
• PPQ and Commercial
batches
Establish analytical comparability retrospectively
between the original clinical batches from CMO
and the scale-up Pilot Plant batches to
1) Show Comparability
2) Set prospective criteria for formal commercial
comparability
Formal comparability protocol to establish
analytical comparability between the PPQ
batches at the commercial site and the
original clinical batches from the CMO

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Ebola Zaire Emergency Use Manufacture Summary
 Supported outbreaks from 2016 – 2020
 ERVEBO  Approved – USA – Dec 19, 2019, EU- Nov. 11, 2019
End to End – 1 year
• Produced >125k doses (10-Dose image)
• Doses available for use – 30Sep2016

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COVID Vaccine Case Study

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Confidential
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G
VSV (Indiana)
RNA genome
N P M G L
1 2 3 4 5
3’ 5’
Merck-IAVI: Employ VSV∆G Virus
Platform Applied to COVID19
VSV = vesicular stomatitis virus
N P M S L
S
VSV∆G-SARS-CoV-2
Replication-competent
chimeric viruses
N P M GP L
VSV∆G-ZEBOV-GP
GP
CHALLENGES
• VSV and CoV are from
different virus families
• VSV and CoV replication
cycles vary considerably
• replicate in different
cellular
compartments
• concentrate in
different regions of
the cell during virus
replication
Plasmid based
recovery to select for
a different G gene

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VSVΔG-SARS-CoV-2 Process Development: Change to the Ebola Zaire
Process
Dispense and
storage
Harvest
Clarification
Filtration
Nuclease
Digestion and
Enzyme
Treatment Ultrafiltration
Cell Seeding and
Passage
Cell Expansion
Ebola Zaire Ph 3 Process
Infection
Zaire Downstream Unit operations
resulted in poor SARS-CoV-2 yields.
Wanted Closed Upstream Operations

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VSVΔG-SARS-CoV-2 Phase 2/3 Process
Dispense and
storage
Eliminates
separate
processing
operation
Cell Seeding and Expansion
Production Bioreactor:
(1) Virus propagation
(2) Nuclease Digestion
Infection
Eliminates
closed
processing
Sterile
Filtration
Clarification
Filtration Ultrafiltration
Column
Chromatography
Conversion to commercial-ready microcarrier process implemented in 3.5 months

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Moving with Speed: Development Timeline for VSVΔG-SARS-CoV-2
Mar
29
Apr
5
Apr
12
Apr
19
Apr
26
May
3
May
10
May
17
May
24
May
31
Jun
7
Jun
14
Jun
21
Jun
28
Jul
5
Jul
12
Jul
19
Jul
26
Aug
2
Aug
9
Aug
16
Aug
23
Aug
30
Sept
6
Sept
13
Sept
20
Sept
27
Oct
4
Oct
11
Oct
18
Oct
25
Nov
1
Nov
8
Nov
15
Nov
22
Nov
29
Jan
31
Dec
6
Dec
13
Dec
20
Dec
27
Jan
3
Jan
10
Feb
7
Jan
16
Jan
24
Phase 1 GMP
DS
Phase 1 FIH 02Nov
Phase 1 Process Development
VSVΔG-SARS-
CoV-2 begins
Clone
Selected
Phase 2/3 Process Development
Phase 3 GMP DS
Phase 2/3 Process Development
VSVDG-SARS-CoV-2 Discontinued
Phase 1 DP
Phase 3 DP
TIME to FIH: 6.5 months
TIME to Ph3 READY: 6 months
Master Virus Seed

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Sudan Vaccine Case Study

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Confidential
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G
VSV (Indiana)
RNA genome
N P M G L
1 2 3 4 5
3’ 5’
Plasmid based
recovery to select for
a different G gene
Merck-IAVI: Employ VSV∆G Virus Platform
For Sudan Vaccine
VSV = vesicular stomatitis virus
N P M GP L
VSV∆G-ZEBOV-GP
GP
VSV∆G-SUDV-GP

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How?
• Rapidly established a partnership with IAVI with boundaryless interactions
• Strong Win as One Team concept
• Capitalized on the strengths within the partnership
• Merck leveraged their VSV Platform to bring speed to the process
• DS available to fill
• Platform DP and Packaging Processes using 10 ml clinical image
• Straight through processing end to end for speed
• Effective knowledge management allowed us to quickly address questions
• Partnered with IAVI and WHO on label design/content
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Analytical Approach
• Ebola Zaire assays used to release Sudan vaccine
• IAVI rapidly developed an identity test using PCR technology
• Strong coordination of analytical teams
• Existing DS stability data allowed ability to fill quickly
• Historical Sudan DP data to establish DP expiration dating
• Strong coordination between Merck, IAVI and contract laboratories to ensure rapid
sample transfer and test execution
• Partnering with contracts labs and IAVI to allow use of Merck assays for IAVI
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Regulatory and Quality Perspective
• Rapid collaboration of Merck and IAVI Quality Teams
• Built trust quickly to identify opportunities to bring speed to the release and filing processes
How?
• Merck established a Quality Agreement with IAVI to frame regulatory and quality processes
• Merck prepared the Pharmacy Manual using historical experience
• Provided ERVEBO® CMC draft sections were provided by Merck, IAVI prepared the clinical
sections for the IND
• Developed a Hybrid release process between Merck and IAVI
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Sudan Vaccine Timeline
October November December January
DP Manufacture
Package and Label
Initiate Discussions
with IAVI
Arrives in Uganda 12/18
Manufacture, Package, Label, Release and Ship Drug Product in 6 weeks!

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Process Development
• Platform processes with standard unit operations can enable faster path to clinic and commercial manufacture
• Minimize repeat scientific work and take reasonable risk-based decisions in development
• Front-load analytical resources to enable rapid process understanding.
Manufacturing
• Design and implement multi-purpose flexible facilities
• Use existing facilities to support PPQ activities and address long term commercial capacity off critical path
Clinical and Regulatory Interactions
• Early engagement with the regulatory agencies for alignment on strategies for product development and licensure
and leverage alternate regulatory approaches
Emergency Use Authorization/PLPA
• Requires advance planning to establish fastest path to clinical efficacy PoC
• Manufacturers must comply with existing regulations
• Quality must not be compromised; EUA does not “shortcut” this!
Lessons Learned to Apply to Future Vaccine Development Programs

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We’re all under the same pressure to get it
right to ensure availability of licensed doses
to support outbreak efforts.

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Acknowledgements
Merck Ebola, COVID and Sudan Teams Lynne Isopi
VPR&D Organization Larry Dick
Beth-Ann Coller Liman Wang
Kristine Fuller Melissa Whiteman
Joe Joyce Brendan Grau
Doug Richardson Chris Grosso
Kim Hassis Melissa Hughes
External partners – IAVI, GAVI, UNICEF, WHO to name a few
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Thank you
and
Questions
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