![Public
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]](https://image.slidesharecdn.com/kayhunsberger-230327060325-753769d9/85/HOW-MERCK-CONTINUES-TO-EXPLORE-SPEEDING-VACCINE-DEVELOPMENT-TIMELINES-14-320.jpg)
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HOW MERCK CONTINUES TO EXPLORE SPEEDING VACCINE DEVELOPMENT TIMELINES
- 1. Public How Merck Continuesto Explore Speeding Vaccine Development Timelines Vaccine Technology Summit March 20 – 21 2023 Kay Hunsberger Executive Director Merck & Co., Inc., Kenilworth, NJ, USA.
- 2. Public Agenda Approach toRapid 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
- 3. Public Typical Timeline forVaccine Development •8 to 12 Years •Standard timeline to develop a vaccine. 2028+ 2020 This timeline is not acceptable for an epidemic or pandemic!
- 4. Public Rapid Product andProcess 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
- 5. Public Transition toward RealTime 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
- 6. Public End to EndAnalytics 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
- 7. Public Manufacturing • Self supportingmanufacturing 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
- 8. Public 8 Adaptive Process Control viaPAT 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
- 9. Public Regulatory Approaches • Manycountries 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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- 11. Public CASE STUDY: EbolaZaire Vaccine 11 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.
- 12. Public Merck’s Approach toAddress 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
- 13. Public Merck’s Vaccine Milestonesand Accelerated Development Timeline
- 14. Public 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]
- 15. Public Ebola Zaire VaccineDrug 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
- 16. Public Ebola Zaire DrugProduct 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
- 17. Public Approach to AnalyticalComparability 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
- 18. Public Ebola Zaire EmergencyUse 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
- 19.
- 20. Public Confidential 20 G VSV (Indiana) RNA genome NP 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
- 21. Public 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
- 22. Public VSVΔG-SARS-CoV-2 Phase 2/3Process 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
- 23. Public 23 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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- 25. Public Confidential 25 G VSV (Indiana) RNA genome NP 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
- 26. Public How? • Rapidly establisheda 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 26
- 27. Public Analytical Approach • EbolaZaire 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 27
- 28. Public Regulatory and QualityPerspective • 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 28
- 29. Public Sudan Vaccine Timeline OctoberNovember 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!
- 30. Public Process Development • Platformprocesses 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
- 31. Public 31 We’re all underthe same pressure to get it right to ensure availability of licensed doses to support outbreak efforts.
- 32. Public Acknowledgements Merck Ebola, COVIDand 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 32
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Editor's Notes
- #9 Finally, process design, scalability, supply chain, and process control come together in the final design of the manufacturing facility. As such, process design elements and decisions made early in development shape the final commercial footprint which is why facility investment can begin very early, sometimes at Ph 1 testing. The so-called “factory-of-the-future” is envisioned to be a flexible multi-product facility enabled by the concepts exemplified here. Continous vaccine processing, while still emerging can enable more rapid turn-over of products within a single facility while single-use technologies and integrated supply chains mean that common elements can be exploited for vaccines which may have different overall processes. Finally, the incorporation of more process analytical technologies will enable greater control and batch success at the floor level.
- #18 Clinical manufacturing of V920 has been performed at CMO and the Biologics Pilot Plant, whereas the intended commercial manufacturing is a different facility. Due to the different sites involved it is necessary to build a robust comparability strategy but due to the unmet medical need for an Ebola vaccine it is essential to do so in an expedited fashion. A 2 step comparability design was proposed. 1) Between the two clinical manufacturing sites and then 2) Between Pilot Plant and Commercial site An analysis of process parameters and data from lots manufactured at the CMO and Biological Pilot Plant was completed in order to evaluate manufacturing consistency and feasibility of process scale-up prior to PPQ at the intended commercial manufacturing facility) The analysis of CMO and Pilot Plant, assessed the consistency of manufacture and identified historical data that could be used to set prospective acceptance criteria for the formal comparability assessment between material manufactured during PPQ at the commercial site and the Pilot Plant. During PPQ at the commercial site , the bulk product and manufacturing process will be assessed the against Critical Quality Attributes (CQA) and Critical Process Parameters (CPP). Due to the timelines communication with the regulatory agencies was a necessity in order to keep the project on track