Date:
`From:
`
`Summary Basis for Regulatory Action
`01/30/2022
`Sudhakar Agnihothram, PhD, Review Committee Chair,
`DVRPA/OVRR
`
`BLA/NDA STN:
`Applicant:
`Submission Receipt Date:
`PDUFA Action Due Date:
`Proper Name:
`Proprietary Name:
`Indication:
`
`STN 125752/0
`ModernaTX Inc.
`August 24, 2021
`April 24, 2022
`COVID-19 Vaccine, mRNA
`SPIKEVAX
`Active immunization to prevent coronavirus disease 2019
`(COVID-19) caused by severe acute respiratory syndrome
`coronavirus 2 (SARS-CoV-2) in individuals 18 years of age
`and older
`
`Recommended Action: The Review Committee recommends approval of this product.
`
`______________________________________________________________________
`Director, Product Office
`
`
`______________________________________________________________________
`Director, Office of Compliance and Biologics Quality
`
`
`Moderna 2154
`BioNTech-Pfizer v. Moderna
`IPR2023-01358
`
`

`

`STN 125752/0—SPIKEVAX
`
`Discipline Reviews
`Chemistry Manufacturing and Controls (CMC)
`CMC Product (OVRR)
`
`Facilities Inspection (OCBQ/DMPQ and
`OVRR/DVP)
`
`Facilities review (OCBQ/DMPQ)
`Lot Release, QC, Test Methods, Product
`Quality (OCBQ/DBSQC)
`
`Clinical
`Clinical (OVRR)
`
`Clinical Diagnostic and Immunogenicity Assay
`Reviewers (OVRR)
`
`Postmarketing safety epidemiological review
`(OBE/DE)
`Real World Evidence (OBE)
`Benefit Risk Assessment (OBE)
`
`BIMO
`Statistical
`Statistical data (OBE/DB)
`Non-Clinical/Pharmacology/Toxicology
`Non-Clinical Pharmacology Reviewers (OVRR)
`
`Toxicology and developmental toxicology (OVRR)
`Labeling
`Promotional (OCBQ/APLB)
`Container and Carton/Package Insert Review
`(OVRR)
`
`Consults (CDISC, Datasets)
`Regulatory Project Management
`(OVRR)
`Advisory Committee Summary
`
`Reviewer / Consultant - Office/Division
`
`Alena Dabrazhynetskaya, PhD, OVRR/DVP
`Sara Gagneten, PhD, OVRR/DVP
`Pankaj (Pete) Amin, OCBQ/DMPQ
`Obinna Echeozo, MPH, MBA, OCBQ/DMPQ
`Christian Lynch, OCBQ/DMPQ
`Anissa Cheung, MS, OVRR/DVP
`Obinna Echeozo, MPH, MBA
`Marie Anderson, PhD
`Emnet Yitbarek, PhD
`Hsiaoling (Charlene) Wang, PhD
`Most Nahid Parvin, PhD
`LCDR Yen Phan, MLS(ASCP)
`
`Rachel Zhang, MD, OVRR/DVRPA
`Jaya Goswami, MD, MA OVRR/DVRPA
`Anuja Rastogi, MD, OVRR/DVRPA
`Swati Verma, PhD, OVRR/DVP
`Keith Peden, PhD, OVRR/DVP
`Sara Gagneten, PhD, OVRR/DVP
`CDR Jane Baumblatt, MD, OBE/DE
`
`Yun Lu, PhD, OBE
`Hong Yang, PhD
`Osman Yogurtcu, PhD
`Patrick Funk, PhD
`Bhanu Kannan, MS, OCBQ/DIS
`
`Ye Yang, PhD, OBE/DB
`
`Keith Peden, PhD, OVRR/DVP
`Li Sheng-Fowler, PhD, OVRR/DVP
`Ching-Long (Joe) Sun, PhD, OVRR/DVRPA
`
`CAPT Oluchi Elekwachi, PharmD, MPH
`Daphne Stewart, OVRR/DVRPA
`Josephine Resnick, PhD, OVRR/DVRPA
`Joseph Kulinski, PhD, OVRR/DVRPA
`Brenda Baldwin, PhD, OVRR/DVRPA
`Josephine Resnick, PhD, OVRR/DVRPA
`Joseph Kulinski, PhD, OVRR/DVRPA
`No Advisory Committee Meeting Held
`
`2
`
`

`

`STN 125752/0—SPIKEVAX
`
`Table of Contents
`1.
`Introduction ........................................................................................................................4
`2. Background ........................................................................................................................4
`3. Chemistry Manufacturing and Controls ...............................................................................6
`a. Product Quality ........................................................................................................6
`b. Testing Specifications ............................................................................................10
`c. CBER Lot Release .................................................................................................11
`d. Facilities Review / Inspection..................................................................................11
`e. Container/Closure System ......................................................................................13
`f. Environmental Assessment ....................................................................................13
`4. Nonclinical Pharmacology/Toxicology ...............................................................................14
`5. Clinical Pharmacology ......................................................................................................15
`6. Clinical/Statistical .............................................................................................................15
`a. Clinical Program.....................................................................................................16
`b. Bioresearch Monitoring (BIMO) – Clinical/Statistical/Pharmacovigilance ..................24
`c. Pediatrics ...............................................................................................................24
`d. Other Special Populations ......................................................................................24
`7. Safety and Pharmacovigilance..........................................................................................25
`8.
`Labeling ...........................................................................................................................28
`9. Advisory Committee Meeting ............................................................................................28
`10. Other Relevant Regulatory Issues.....................................................................................28
`11. Recommendations and Benefit/Risk Assessment ..............................................................28
`a. Recommended Regulatory Action ..........................................................................28
`b. Benefit/Risk Assessment ........................................................................................28
`c. Recommendation for Postmarketing Activities.........................................................29
`
`3
`
`

`

`STN 125752/0—SPIKEVAX
`
`1. Introduction
`ModernaTX, Inc. submitted an original Biologics License Application (BLA) STN BL 125752 for
`licensure of COVID-19 Vaccine, mRNA. The proprietary name of the vaccine is SPIKEVAX™.
`SPIKEVAX is a vaccine indicated for active immunization to prevent coronavirus disease 2019
`(COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in
`individuals 18 years of age and older. The vaccine is administered intramuscularly (IM) as a
`series of two doses (0.5 mL each) one month apart.
`
`SPIKEVAX (also referred to in this document as “mRNA-1273 vaccine” in discussions related to
`non-clinical and clinical development, or as “Moderna COVID-19 Vaccine” during use under
`EUA) contains a nucleoside-modified messenger RNA (mRNA) encoding the pre-fusion
`stabilized spike (S) glycoprotein of SARS-CoV-2 that is encapsulated in a lipid nanoparticle
`(LNP) composed of four lipids: SM-102, polyethylene glycol [PEG] 2000 dimyristoyl glycerol
`[DMG], cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC]. The mode of action
`is based on delivery of the mRNA-LNPs into host cells to allow expression of the SARS-CoV-2 S
`antigen. The vaccine elicits an immune response to the S antigen, which protects against
`COVID-19.
`
`SPIKEVAX is provided as a sterile, white to off-white suspension for intramuscular injection.
`Each 0.5 mL vaccine dose is formulated to contain 0.1 mg mRNA in buffered sucrose. The
`vaccine does not contain preservatives, antibiotics, adjuvants, human-derived or animal-derived
`materials.
`
`SPIKEVAX is supplied in two multiple-dose vial presentations in 10 mL vials that are closed with
`a rubber stopper and aluminum crimp flip-off seal. The two SPIKEVAX presentations are: a
`-mL fill volume containing a maximum of 11 doses per vial and an
`-mL fill volume
`containing a maximum of 15 doses per vial. The vaccine is stored frozen between -50 to -15ºC
`but can be stored refrigerated between 2 to 8°C for up to 30 days prior to first use. Prior to
`administration, the vaccine should be thawed in refrigerated conditions between 2 to 8°C for 2.5
` mL fill volume) and kept at room temperature for 15
`hours
` mL fill volume) and 3 hours
`minutes before administration. Alternatively, it can be thawed at room temperature between 15 to
` mL fill volume) and 1.5 hours
`25ºC for 1 hour
` mL fill volume). After the first dose has been
`withdrawn, the vial should be held between 2 to 25ºC and should be used within 12 hours.
`
`The expiry for SPIKEVAX supplied in multiple dose vials is 9 months from the date of
`manufacture when stored at -25 to -15°C. The date of manufacture is defined as the date of final
`sterile filtration of the formulated drug product (DP). Following the final sterile filtration, no
`reprocessing/reworking is allowed without prior approval from the FDA.
`2. Background
`SARS-CoV-2 is a zoonotic coronavirus that emerged in late 2019 and was identified in patients
`with pneumonia of unknown cause. The virus was named SARS-CoV-2 because of its similarity
`to the coronavirus responsible for severe acute respiratory syndrome (SARS-CoV, a lineage B
`betacoronavirus). SARS-CoV-2 is an enveloped, positive-sense, single-stranded RNA virus
`sharing more than 70% of its sequence with SARS-CoV, and ~50% with the coronavirus
`responsible for Middle Eastern respiratory syndrome (MERS-CoV). SARS-CoV-2 is the causative
`agent of COVID-19, an infectious disease with respiratory and systemic manifestations. Disease
`symptoms vary, with many persons presenting with asymptomatic or mild disease and some
`progressing to severe respiratory tract disease including pneumonia and acute respiratory
`distress syndrome, leading to multiorgan failure and death.
`
`4
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
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`(b) (4)
`
`

`

`STN 125752/0—SPIKEVAX
`
`
`The SARS-CoV-2 pandemic continues to present a challenge to global health and, as of
`January,14, 2022, has caused approximately 318 million cases of COVID-19, including 5.58
`million deaths worldwide. In the United States, more than 65 million cases and 847,000 deaths
`have been reported to the Centers for Disease Control and Prevention (CDC). While the
`pandemic has caused morbidity and mortality on an individual level, the continuing spread of
`SARS-CoV-2, and emerging variants such as the Delta variant and the more recently identified
`Omicron variant now predominant in the U.S., have caused significant challenges and
`disruptions in worldwide healthcare systems, economies, and many aspects of human activity
`(travel, employment, education).
`
`In December 2020, the FDA issued emergency use authorizations (EUAs) for two mRNA
`vaccines which encode the SARS-CoV-2 S glycoprotein: Pfizer-BioNTech COVID-19 Vaccine
`(manufactured by Pfizer, Inc. in partnership with BioNTech Manufacturing GmbH) for use in
`individuals 16 years of age and older and Moderna COVID-19 Vaccine (manufactured by
`ModernaTX, Inc.) for use in individuals 18 years of age and older. In February 2021, the FDA
`issued an EUA for a replication-incompetent adenovirus type 26 (Ad26)-vectored vaccine
`encoding a stabilized variant of the SARS-CoV-2 S glycoprotein, manufactured by Janssen
`Biotech, Inc. (Janssen COVID-19 Vaccine) for use in individuals 18 years of age and older.
`
`In 2021, the FDA expanded the EUAs for:
`
`
`• The Pfizer-BioNTech COVID-19 Vaccine to include a two-dose primary series in
`individuals 5 years of age and older, a third primary series dose for individuals 5 years of
`age and older with certain immunocompromising conditions, and a single booster dose in
`individuals 12 years of age and older.
`• The Moderna COVID-19 Vaccine to include a third primary series dose for individuals 18
`years of age and older with certain immunocompromising conditions, and a single
`booster dose in individuals 18 years of age and older.
`• The Janssen COVID-19 Vaccine to include a single booster dose in individuals 18 years
`of age and older.
`
`All three vaccines were also authorized for use as a heterologous (or “mix and match”) booster
`dose following completion of primary vaccination with an another available COVID-19 vaccine.
`
`Several therapies, including antivirals, SARS-CoV-2 -targeting monoclonal antibodies, immune
`modulators and convalescent plasma, are available under emergency use.
`
`On August 23, 2021, the Pfizer-BioNTech COVID-19 Vaccine was approved for use in
`individuals 16 years of age and older under the trade name COMIRNATY.
`
`Following EUA of COVID-19 vaccines in December 2020, COVID-19 cases and deaths in the
`United States declined sharply during the first half of 2021. The emergence of the Delta variant,
`variable implementation of public health measures designed to control spread, and continued
`transmission among unvaccinated individuals were major factors in the resurgence of COVID-19
`leading to the Delta variant-associated peak in September of 2021. Following the report of the
`first U.S. case of COVID-19 attributed to the Omicron variant on December 1, 2021, daily
`numbers of new cases in the U.S. increased sharply, rising by about 540% in 6 weeks. Given the
`current winter season with more indoor activities due to cold weather, there is concern that the
`trend of increasing cases may continue.
`
`The regulatory history of SPIKEVAX is summarized in Table 1.
`
`
`
`5
`
`

`

`STN 125752/0—SPIKEVAX
`
`Table 1. Regulatory History
`Regulatory Events / Milestones
`Pre-IND meeting
`IND submission
`
`Date
`February 19, 2020
`IND 19635 for Phase 1 Study: February 20, 2020
`
`Fast Track designation granted
`Pre-BLA meeting
`
`IND 19745 for Phase 2 Study: April 27, 2020
`May 11, 2020
`April 28, 2021, Clinical
`July 1, 2021, CMC/Regulatory
`BLA 125752/0 submission
`August 24, 2021
`BLA filed
`October 14, 2021
`Mid-Cycle communication
`The Applicant cancelled
`Late-Cycle meeting
`The Applicant cancelled
`Action Due Date
`April 24, 2022
`3. Chemistry Manufacturing and Controls
`a. Product Quality
`Description of Active Ingredient
`SPIKEVAX is an mRNA-based vaccine indicated for active immunization for prevention of
`COVID-19. The mRNA in SPIKEVAX is called mRNA-1273 and is comprised of an open reading
`frame of 3819 nucleotides encoding the full-length S glycoprotein (from Wuhan-Hu-1 isolate of
`SARS-CoV-2 virus) modified to introduce two proline residues that stabilize the S glycoprotein in
`pre-fusion conformation. The mRNA also contains four regulatory elements: 5’ and 3’
`untranslated regions (UTRs) which increase translational fidelity and confer robust protein
`expression, a 3’ poly(A) tail sequence which promotes mRNA stability, and a 5’ cap structure
` which mediates efficient translation. The mRNA is transcribed using N1-
`methyl-pseudoruridine instead of uridine nucleoside to minimize indiscriminate recognition of
`exogenous mRNA by pathogen-associated cellular receptors and to reduce the overall
`reactogenicity of synthetic mRNA. The in vitro transcribed single-stranded mRNA is
`encapsulated in a lipid nanoparticle
` composed of four lipids: SM-102 (a custom-
`manufactured, ionizable lipid); PEG2000-DMG; cholesterol, and DSPC. SPIKEVAX multiple-
`dose vials contain a frozen suspension that does not contain a preservative and must be thawed
`prior to administration.
`
`SPIKEVAX Manufacturing Overview
`The manufacturing process for SPIKEVAX drug substance (DS) consists of
`
`containers, and labeling/packaging.
`
` The SPIKEVAX DP is manufactured by
` filling of final
`
`Drug Substance
`Manufacture of CX-024414 mRNA
`The CX-024414 mRNA manufacturing process consists of
`
`6
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`STN 125752/0—SPIKEVAX
`
`
`
`
`
`
`
`Manufacturing Process Development - CX-024414 mRNA
`The manufacturing process for CX-024414 mRNA was developed progressively to support
`clinical development, emergency use authorization, and commercial supply. The initial process
`was developed in the ModernaTX
`
`
`
`
`
`
`
`
`
`
`
`To support increases in manufacturing capacity, the process underwent scale-related changes,
`denoted as Scale A
` initial Scale B
` and commercial Scale B
`
`
`. The defined increases in scale included
` The major process changes implemented between the
`
` and Scale A include
`
`.
`
`Subsequent unit operations remained consistent from Scale A through commercial Scale B.
`
`Comparability Assessment - CX-024414 mRNA
`Comparability of Scale A, initial Scale B, and commercial Scale B processes was demonstrated
`through a) analytical comparability assessment by release, extended characterization, and
`stability testing and b) process performance comparability assessment by in-process controls
`(IPCs) and critical process parameters (CPPs) evaluated against expected ranges or proven
`acceptance ranges (PARs). All release results obtained for process performance qualification
`(PPQ) batches manufactured using commercial Scale B process
`
`conformed to both the specification and comparability acceptance criteria across all lots
`manufactured with different process trains at ModernaTX and Lonza sites. All results for
`extended analytical characterization conformed to the comparability expected range. The
`process comparability results showed that the Scale B manufacturing process parameters and
`quality attributes were comparable across the manufacturing sites.
`
`
`
`
`
`
`
`
`
`
`7
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`
`
`
`
`
`
`
`
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`
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
`
`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

`

`STN 125752/0—SPIKEVAX
`
`Manufacture of mRNA-1273 LNP DS
`The mRNA-1273 LNP DS manufacturing process consists of
`
`Manufacturing Process Development - mRNA-1273 LNP DS
`The mRNA-1273 LNP DS manufacturing process
`
` To support increases in manufacturing capacity at ModernaTX,
`
`support the commercial supply,
`
`. The analytical methods for the mRNA-1273 LNP
`DS release and stability testing were changed concurrently with process development.
`
`To
`
`Comparability Assessment - mRNA-1273 LNP DS
`The comparability studies for mRNA-1273 LNP DS were performed
`. Analytical comparability of commercial Scale B process
`
`was demonstrated through
`
`ModernaTX and Lonza. All release results
`conformed to both the specification and comparability acceptance criteria for all PPQ lots tested.
`The extended characterization data conformed to the expected ranges for all attributes tested. All
`CPP, CIPC, and IPC values for all process comparability lots across the two manufacturing sites
`met their PARs and expected outcomes, supporting consistent performance for commercial
`production of mRNA-1273 LNP DS.
`
`Drug Product
`The SPIKEVAX DP, is an mRNA-lipid complex suspension of an mRNA encapsulated in lipid
`particles. The SPIKEVAX DP is a sterile, preservative-free solution that contains 0.20 mg/mL
`CX-024414 mRNA and 3.87 mg/mL SM-102 LNPs in a buffer containing 20 mM Tris; 87 g/L
`8
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
`
`

`

`
` mM acetate, pH 7.5 (Table 2). The SPIKEVAX DP is supplied as a multiple-
`sucrose; and
`dose, ready-to-use suspension for intramuscular administration in 10-mL vials that are closed
`with a rubber stopper and aluminum crimp flip-off seal.
`
`STN 125752/0—SPIKEVAX
`
`Table 2. SPIKEVAX Drug Product Composition
`
`Unit Formula
`(mg/mL)
`
`Unit Formula
`(mg/vial)
`-mL fill)
`
`(
`
`Unit Formula
`(mg/vial)
`-mL fill)
`
`(
`
`Unit Formula
`(mg/dose) (0.5
`mL dose)
`
`0.20
`
`
`
`
`
`0.10
`
`Component
`CX-024414 mRNA
`
`SM-102
`LNP
`
`Function
`mRNA that encodes for
`the pre-fusion stabilized
`Spike glycoprotein of
`2019-novel Coronavirus
`(SARS-CoV-2)
`Lipid Nanoparticles (The
`individual lipids make up
`the Lipid Components of
`the SM-102 LNP)
`
`
`
`SM-102
`Cholesterol
`DSPC
`PEG2000-
`DMG
`Tromethamine (Tris)
`Components in
`Tromethamine HCl (Tris-
`Tris buffer
`HCl)
`Buffer components for
`Acetic acid
`Sodium Acetate buffer in
`Sodium acetate
`LNP
`trihydrate
`87
`Cryoprotection
`Sucrose
`
`q.s. 1.0 mL
`Diluent
`Water for injection
`Abbreviations: DSPC = 1,2-distearoyl-sn-glycero-3-phosphocholine; q.s. = quantum sufficit
`
`3.87
`
`0.61
`2.35
`
`0.085
`0.39
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`0.31
`1.18
`
`0.043
`0.20
`
`43.5
`q.s. 0.5 mL
`
`
`
`Manufacture of SPIKEVAX DP
`The SPIKEVAX DP manufacturing processes at Catalent and Baxter facilities are very similar
`and consist of the same unit operations, i.e.,
`
`Manufacturing Process Development
`Manufacturing process development for SPIKEVAX DP
` at ModernaTX and
`Scale A process,
` at Catalent (Bloomington, IN). To support
`then scaled
`emergency use authorization and commercial supply, the commercial Scale B process at
`Catalent
`
`.
`
`
`
`
`
`
`
`
`). The analytical methods were developed concurrently with
`process development. No changes have been implemented that impact the comparison of data
`generated from the tests for the purpose of comparability assessment and comparison between
`the clinical development and commercial lots.
`
`Comparability Assessment
`For comparison between manufacturing scales, the SPIKEVAX DP analytical comparability was
`assessed using relevant release, stability, and extended characterization testing against pre-
`9
`
`
`
`
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`
`
`(b) (4)
`
`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

`STN 125752/0—SPIKEVAX
`
`
`defined acceptance criteria. CPP and IPC results were also evaluated against expected ranges
`for demonstration of the process performance comparability. To establish the expected analytical
`ranges, the initial baseline comparability studies (Phase 1) were performed using development,
`clinical, GMP, and PPQ batches.
`
`The post-change comparability of the commercial Scale B process was assessed in Phase 2 and
`Phase 3 studies that were performed at Catalent and Baxter manufacturing sites. All CPP,
`CIPCs, and IPCs established for the commercial process met their PARs and expected ranges,
`demonstrating consistent performance for commercial production of SPIKEVAX DP using all
`filling lines at both manufacturing sites. Release testing of PPQ lots was performed in
`accordance with the specifications established for each fill presentation. Overall, the results from
`the Scale B
`-mL and
`-mL fill presentation DP batches manufactured at Catalent on all
` fill lines
` and the results from Scale B
`-mL fill
`presentation DP batches manufactured at Baxter on
` demonstrated that the pre-
`change and post-change manufacturing process and quality attributes are comparable.
`
`Stability Summary and Conclusion and Stability Data
`An initial shelf life of 9 months is proposed for the SPIKEVAX DP lots stored in the commercial
`container-closure systems at the recommended long-term storage condition of -25 to -15°C
`(-20°C). The proposed shelf life includes up to 1 month (30 days) of storage at 2 to 8°C (5°C)
`and up to 24 hours at room temperature (25°C) to support administration of the vaccine at the
`point of care site.
`
`b. Testing Specifications
`
`The tests and specifications applied for routine release of SPIKEVAX are shown in Table 3.
`
`Acceptance Criteria
`White to off-white dispersion. May contain visible,
`white or translucent product-related particulates
`
`
`Table 3. Testing Specifications for SPIKEVAX
`Test
`Method
`Appearance
`Visual
`
`Identity
`
`Total RNA Content
`
`Purity
`Product-Related Impurities
`
`
`
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`
`
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`
`
`
`
`%RNA
`
`
`
`Particle Size
`
`
`
`
`
`
`
`
`
`
`
`10
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

`

`Method
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`Test
`
`
`
`SM-102
`Cholesterol
`DSPC
`PEG2000-DMG
`
`SM-102
`Cholesterol
`DSPC
`PEG2000-DMG
`Lipid Impurity
`
`pH
`
`
`
`
`Container Contenta
`
`Bacterial Endotoxins
`
`
`
`
`
`
`Sterility
`Container-Closure Integrity
`(Stability only)
`a Container content is measured based on SOP-1229
`Option A:
`
`
`
`
`
`Option B:
`
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`STN 125752/0—SPIKEVAX
`
`Acceptance Criteria
`
`
`
`
`
`
`Individual Impurities:
`Total impurities:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Maximum 11 Dose (0.5 mL per dose) Presentation
`Syringe/Needle:
`Option A: 11 doses of 0.5 mL from 1 vial
`Option B: 10 doses of 0.5 mL from 1 vial
`Maximum 15 Dose (0.5 mL per dose) Presentation
`Syringe/Needle:
`Option A: 15 doses of 0.5 mL from 1 vial
`Option B: 13 doses of 0.5 mL from 1 vial
`
`
`Release
`No growth
`End of Shelf Life
`Pass
`
`
`
`
`
`
`
`
`
`
`
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`The analytical methods and their validation and/or qualification for the SPIKEVAX DS and DP
`were found to be adequate for release testing and stability monitoring.
`
`c. CBER Lot Release
`
`The lot release protocol template was found to be acceptable after revisions. A lot release testing
`plan was developed by CBER and will be used for routine lot release.
`
`d. Facilities Review / Inspection
`
`Facility information and data provided in the BLA were found to be sufficient and acceptable. The
`facilities involved in the manufacture of the Moderna COVID-19 Vaccine are listed in Table 4.
`The activities performed and inspectional histories are noted in the table.
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`STN 125752/0—SPIKEVAX
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`Table 4. Manufacturing Facilities Table for SPIKEVAX (COVID-19 Vaccine, mRNA)
`FEI
`DUNS
`Inspection/
`number
`number
`waiver
`
`Name/Address
`Aldevron, LLC
`4055 41st Avenue
`South Fargo, ND 58104
`
`3015047170
`
`048764943
`
`Pre-License
`Inspection (PLI)
`
`Justification
`/Results
`
`CBER
`November 1 – 5,
`2021
`NAI
`
`ModernaTX, Inc.
`One Moderna Way
`Norwood, MA 02062
`
`Drug Substance
`mRNA and LNP manufacture
`
`Drug Product
`Release Testing
`Lonza Biologics, Inc.
`101 International Drive
`Portsmouth, NH 03801
`
`Drug Substance
`mRNA and LNP manufacture
`Catalent Indiana, LLC (subsidiary of
`Catalent Pharma Solutions, LLC)
`(Catalent)
`1300 S Patterson Drive
`Bloomington, IN 47403
`
`Drug Product
`Fill/finish, labeling, packaging and
`release testing (sterility)
`Baxter Pharmaceutical
`Solutions, LLC (Baxter)
`927 S. Curry Pike
`Bloomington, IN 47403
`
`Drug Product
`Fill/finish, labeling, packaging and
`release testing (sterility)
`
`3014937058
`
`116912313
`
`PLI
`
`3001451441
`
`093149750
`
`PLI
`
`3005949964
`
`172209277
`
`Waived
`
`1000115571
`
`604719430
`
`Waived
`
`CBER
`October 25 – 29,
`2021
`NAI
`
`CBER
`October 18 – 22,
`2021
`VAI
`
`CDER
`August 27 –
`September 02,
`2020
`VAI
`
`ORA/OBPO
`November 02 –
`10, 2021
`VAI
`
`ORA
`
`Drug Product
`Release testing (bacterial endotoxin)
`Abbreviations: DUNS = Data Universal Numbering System; FEI = FDA Establishment Identifier; LNP = lipid nanoparticle; NAI = no
`action indicated = ORA, Office of Regulatory Affairs; OBPO = Office of Biological Products Operations; VAI = voluntary action
`indicated
`
`VAI
`
`Waived
`
`CBER conducted a Pre-License Inspection (PLI) of Aldevron, LLC in November 2021. No Form
`FDA 483 was issued, and the inspection was classified as no action indicated (NAI).
`
`CBER performed a PLI of ModernaTX, Inc. in October 2021. No Form FDA 483 was issued, and
`the inspection was classified NAI.
`
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`

`STN 125752/0—SPIKEVAX
`
`
`
`CBER conducted a PLI of Lonza Biologics, Inc. in October 2021 and a Form FDA 483 was
`issued at the end of the inspection. The firm responded to the observations and the corrective
`actions were reviewed and found to be adequate. All inspectional issues were resolved, and the
`inspection was classified voluntary action indicated (VAI).
`
`CDER inspected the Catalent facility in Bloomington, IN for a different drug product. This PLI was
`conducted in August/September 2020. Catalent is one of two Contract Manufacturing
`Organizations responsible for fill/finish operations, release, and stability testing of SPIKEVAX. A
`Form FDA 483 was issued at the end of the inspection. All inspectional issues were resolved,
`and the inspection was classified VAI.
`
`ORA/OBPO performed a surveillance inspection of the Baxter facility in Bloomington, IN in
`November 2021. A Form FDA 483 was issued at the end of the inspection. All inspectional
`issues were resolved, and the inspection was classified VAI.
`
`
`ORA performed a surveillance inspection of
`. A Form FDA 483 was issued at the end of the inspection. All inspectional
`issues were resolved, and the inspection was classified as VAI.
`
`e. Container/Closure System
`
`The commercial multiple-dose SPIKEVAX DP lots are supplied in a primary container closure
`system consisting of three components (vial, stopper, and seal) configured as shown in Table 5.
`The bulk DP is dispensed into vials and closed with a 20-mm stopper and 20-mm aluminum seal.
`Vials are then packaged in a secondary carton containing a total of 10 DP vials per carton. Each
`carton is then placed into a case containing a total of 12 cartons.
`
`Table 5. Container Closure Configurations for Multiple Dose mRNA-1273 DP Vials
`Container
`Closure
`Component
`Vial
`
`Abbreviation
`
`Description
` 10R clear Type 1 borosilicate glass vials
` 10-mL
` vial, RTU, sterile
` 10R clear Type 1 equivalent alkali
`aluminosilicate glass vial
` 10R clear Type 1 borosilicate glass vial
`
`
`Vial
`Vial
`
`Vial
`Stopper
`
`Stopper
`
`Seal
`
`20 mm
` stopper
`
`
`
`20 mm
` stopper
` 20
`seal with flip-off plastic cap
`
`
`
`
`
`
`
` aluminum
`
`20 mm aluminum seal
`
`f. Environmental Assessment
`
`The BLA included a request for categorical exclusion from an Environmental Assessment under
`21 CFR 25.31. The FDA concluded that this request is justified, and no extraordinary
`circumstances exist that would require an environmental assessment.
`
`
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`

`STN 125752/0—SPIKEVAX
`
`4. Nonclinical Pharmacology/Toxicology
`
`Developmental Assessment and Reproductive Toxicology (DART) Study
`In a developmental toxicity study, 0.2 mL of a vaccine formulation containing nucleoside-modified
`mRNA (100 mcg) and other ingredients that are included in a 0.5-mL single human dose of
`SPIKEVAX was administered IM to female rats on four occasions: 28 and 14 days prior to
`mating, and on gestation days 1 and 13. No vaccine-related fetal malformations or variations and
`no adverse effect on postnatal development were observed in the study. Immunoglobulin G (IgG)
`responses to the pre-fusion stabilized spike protein antigen following immunization were
`observed in maternal samples and F1 generation rats indicating transfer of antibodies from
`mother to fetus and from mother to nursing pups.
`
`Non-GLP Repeat Dose Toxicity and Immunogenicity Study
`The report from a non-good laboratory practice (GLP) repeat-dose toxicity and immunogenicity
`study of IM injection of different dose levels of mRNA-1273 vaccine in rats was submitted and
`reviewed under the BLA. In this study, four groups of rats (5/sex/group) received two tri-weekly
`IM administrations of control article (Tris/sucrose buffer), 30, 60, or 100 mcg of mRNA-1273
`vaccine. A dose-dependent finding of edema at the injection site with or without hindlimb
`impairment was noted in all treated animals starting 24 hours after each dose and resolved by
`end of the week. Dose-independent hematological changes consistent with inflammation
`included marked increases in neutrophil and eosinophil counts in all treatment animals. Slight,
`non-dose-dependent elevations of triglycerides and cholesterol were noted in male rats.
`Antibodies to the spike protein were demonstrated in sera obtained on day 13 post Dose 2. No
`organ weight, gross pathology, or histologic examinations were evaluated in this study. Findings
`from the intramuscular repeat dose rat toxicity study demonstrated that vaccine doses of up to
`100 mcg (two doses given three weeks apart) were well-tolerated.
`
`Other Supportive Toxicology Studies
`The safety of SPIKEVAX is further supported by the aggregate rat repeat-dose toxicity profiles
`observed in six GLP toxicity studies of five vaccines formulated in SM-102 lipid particles
`containing mRNAs encoding various viral glycoprotein antigens, demonstrating tolerance of
`repeat doses of these vaccines without any detrimental effects. Three other toxicology studies
`were also reviewed in support of safety of SPIKEVAX. A study report from an in vitro rat
`micronucleus assay evaluating the genotoxic potential of
` mRNA in SM-102 LNP
`revealed no genotoxic effects of SM-102 LNP. In addition, study reports from a bacterial reverse
`mutation test and an in vitro mammalian cell micronucleus test of PEG2000-DMG were also
`reviewed. No genotoxic effects of PEG2000-DMG were observed in these studies.
`
`Biodistribution Study
`A biodistribution study was not performed with mRNA-1273 v