Decision

Summary of Public Assessment Report for Nuvaxovid dispersion for injection

Updated 22 December 2023

The Public Assessment Report summarises the initial assessment at the time of approval in February 2022. The text in the original report remains unchanged.

Our advice is regularly updated on the basis of significant new data and our latest advice can be found in the Summary of Product Characteristics.

Public Assessment Report - National Procedure - Nuvaxovid dispersion for injection

PLGB 54180/0002

COVID-19 Vaccine (recombinant, adjuvanted)

Novavax CZ a.s.

Full Dossier, Regulation 50 2

Lay summary - Nuvaxovid dispersion for injection - COVID-19 Vaccine (recombinant, adjuvanted)

This is a summary of the Public Assessment Report (PAR) for Nuvaxovid dispersion for injection. It explains how this product was assessed and its authorisation recommended, as well as its conditions of use. It is not intended to provide practical advice on how to use this product. For practical information about using Nuvaxovid dispersion for injection, patients should read the Patient Information Leaflet (PIL) or contact their doctor or pharmacist.

What is Nuvaxovid dispersion for injection and what is it used for?

This application is a full-dossier application. This means that the results of pharmaceutical, non-clinical and clinical tests have been submitted to show that this medicine is suitable for treating the specified indications.

Nuvaxovid dispersion for injection is a vaccine used to prevent COVID-19 caused by the SARS-CoV-2 virus in adults 18 years of age and older.

How does Nuvaxovid dispersion for injection work?

Nuvaxovid dispersion for injection is a vaccine used to prevent COVID-19 caused by the SARS-CoV-2 virus and is given to adults 18 years of age and older.

The vaccine causes the immune system (the body’s natural defences) to produce antibodies and specialised white blood cells that work against the virus, to give protection against COVID-19. None of the ingredients in this vaccine can cause COVID-19.

How is Nuvaxovid dispersion for injection used?

The pharmaceutical form of this medicine is dispersion for injection and the route of administration is injection.

Nuvaxovid dispersion for injection is administered intramuscularly as a course of 2 doses of 0.5 mL each. It is recommended to administer the second dose 3 weeks after the first dose (see section 5.1).

There are no data available on the interchangeability of Nuvaxovid with other COVID-19 vaccines to complete the primary vaccination course. Individuals who have received a first dose of Nuvaxovid should receive the second dose of Nuvaxovid to complete the vaccination course.

No dose adjustment is required in elderly individuals ≥ 65 years of age.

For further information on how Nuvaxovid dispersion for injection is used, refer to the PIL and Summary of Product Characteristics (SmPC) available on the Medicines and Healthcare products Regulatory Agency (MHRA) website.

This medicine can only be obtained with a prescription.

The patient should ask the administering healthcare practitioner if they have any questions concerning the medicine.

What benefits of Nuvaxovid dispersion for injection have been shown in studies?

The clinical efficacy, safety, and immunogenicity of Nuvaxovid dispersion for injection is being evaluated in two pivotal, placebo-controlled, Phase 3 studies, one conducted in North America and one in the United Kingdom, and a Phase 2a/b study conducted in South Africa.

Study 1 (2019nCoV-301)

Study 1 is an ongoing Phase 3, multicentre, randomised, observer-blinded, placebo-controlled study in participants 18 years of age and older in United States and Mexico.

The primary efficacy analysis population (referred to as the Per-Protocol Efficacy [PP-EFF] analysis set) included 25,452 participants who received either Nuvaxovid (n = 17,312) or placebo (n = 8,140), received two doses (Dose 1 on day 0; Dose 2 at day 21, median 21 days [IQR 21-23], range 14-60), did not experience an exclusionary protocol deviation, and did not have evidence of SARS-CoV-2 infection through 7 days after the second dose.

Vaccine efficacy of Nuvaxovid dispersion for injection to prevent the onset of COVID-19 from seven days after Dose 2 was 90.4% (95% CI 82.9 – 94.6). Patients who took Nuvaxovid dispersion for injection (n=17,312) did not experience severe COVID-19 compared with 4 cases of severe COVID-19 reported in patients who took placebo (n=8,140) in the PP-EFF analysis set.

Nuvaxovid dispersion for injection showed similar efficacy in subgroup analyses for male and female participants and racial groups, and across participants with medical comorbidities associated with high risk of severe COVID-19.

The most common Variant of Concern identified during the time period of enrolment of this study was Alpha.

Study 2 (2019nCoV-302)

Study 2 is an ongoing Phase 3, multicentre, randomised, observer-blinded, placebo-controlled study in participants 18 to 84 years of age in the United Kingdom.

The PP-EFF included 14,039 participants who received either Nuvaxovid dispersion for injection (n = 7,020) or placebo (n = 7,019), received two doses (Dose 1 on day 0; Dose 2 at median 21 days (IQR 21-23), range 16-45, did not experience an exclusionary protocol deviation, and did not have evidence of SARS-CoV-2 infection through 7 days after the second dose.

Vaccine efficacy of Nuvaxovid dispersion for injection to prevent the onset of COVID-19 from seven days after Dose 2 was 89.7% (95% CI 80.2 – 94.6). Patients who took Nuvaxovid dispersion for injection (n=7,020) did not experience severe COVID-19 compared with 4 cases of severe COVID-19 reported in patients who took placebo (n=7,019) in the PP-EFF analysis set.

Overall, 431 participants were co-vaccinated with inactivated seasonal influenza vaccines; 217 sub-study participants received Nuvaxovid dispersion for injection and 214 received placebo.

Study 3 (2019nCoV-501)

Study 3 is an ongoing Phase 2a/b, multicentre, randomised, observer-blinded, placebocontrolled study in HIV-negative participants 18 to 84 years of age and people living with HIV (PLWH) 18 to 64 years of age in South Africa. PLWH were medically stable (free of opportunistic infections), receiving highly active and stable antiretroviral therapy, and having an HIV-1 viral load of < 1000 copies/mL.

The PP-EFF included 2,770 participants who received either Nuvaxovid dispersion for injection (n = 1,408) or placebo (n = 1,362), received two doses (Dose 1 on day 0; Dose 2 on day 21), did not experience an exclusionary protocol deviation, and did not have evidence of SARS-CoV-2 infection through 7 days after the second dose.

A total of 147 symptomatic mild, moderate, or severe COVID-19 cases among all adult participants, seronegative (to SARS-CoV-2) at baseline, were accrued for the complete analysis of the primary efficacy endpoint.

Vaccine efficacy of Nuvaxovid dispersion for injection to prevent the onset of COVID-19 from seven days after Dose 2 was 48.6% (95% CI 28.4 –63.1). There were 51 COVID-19 cases (3.62%) in patients who took Nuvaxovid dispersion for injection (n=1,408) compared with 96 COVID-19 cases (7.05%) in patients who took placebo (n=1,362) in the PP-EFF analysis set.

The most common Variant of Concern identified during the time period of enrolment of this study was Beta.

What are the possible side effects of Nuvaxovid dispersion for injection?

For the full list of all side effects reported with this medicine, see Section 4 of the PIL or the SmPC available on the MHRA website.

If a patient gets any side effects, they should talk to their doctor, pharmacist or nurse. This includes any possible side effects not listed in the product information or the PIL that comes with the medicine. Patients can also report suspected side effects themselves, or a report can be made on behalf of someone else they care for, directly via the Yellow Card scheme or search for ‘MHRA Yellow Card’ online. By reporting side effects, patients can help provide more information on the safety of this medicine.

The most common side effects with Nuvaxovid dispersion for injection (which may affect more than 1 in 10 people) are headache, feeling sick (nausea) or getting sick (vomiting), muscle ache, joint pain, tenderness or pain where the injection is given, feeling very tired (fatigue) and generally feeling unwell.

Why was Nuvaxovid dispersion for injection approved?

It was concluded that Nuvaxovid dispersion for injection has been shown to be effective in the prevention of COVID-19 caused by the SARS-CoV-2 virus in adults 18 years of age and older. Furthermore, the side effects observed with use of this product products are considered to be typical for this type of treatment. Therefore, the MHRA decided that the benefits are greater than the risks and recommended that this medicine can be approved for use.

Nuvaxovid dispersion for injection has been authorised with a Conditional Marketing Authorisation (CMA). CMAs are intended for medicinal products that address an unmet medical need, such as a lack of alternative therapy for a serious and life-threatening disease.

CMAs may be granted where comprehensive clinical data is not yet complete, but it is judged that such data will become available soon.

What measures are being taken to ensure the safe and effective use of Nuvaxovid dispersion for injection?

As for all newly authorised medicines, a Risk Management Plan (RMP) has been developed for Nuvaxovid dispersion for injection. The RMP details the important risks of Nuvaxovid dispersion for injection, how these risks can be minimised, any uncertainties about Nuvaxovid dispersion for injection (missing information), and how more information will be obtained about the important risks and uncertainties.

The following safety concerns have been recognised for Nuvaxovid:

Important identified risks	None
Important potential risks	Vaccine-associated enhanced disease (VAED) (including vaccine associated enhanced respiratory disease [VAERD]), anaphylaxis, myocarditis and pericarditis
Missing information	Use in pregnancy and while breastfeeding, use in immunocompromised patients, use in frail patients with comorbidities (e.g., chronic obstructive pulmonary disease (COPD), diabetes, chronic neurological disease, cardiovascular disorders), use in patients with autoimmune or inflammatory disorders, interaction with other vaccines, long-term safety

The applicant proposes the continuation of safety surveillance from 4 ongoing clinical trials:

• 2019nCoV-101; A 2-part, Phase 1/2, Randomized, Observer-Blinded Study to Evaluate the Safety and Immunogenicity of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine (SARS-CoV-2 rS) With or Without Matrix-M Adjuvant in Healthy Subjects

• 2019nCoV-501; A Phase 2a/b, Randomized, Observer-Blinded, Placebo-Controlled Study to Evaluate the Efficacy, Immunogenicity, and Safety of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine (SARS-CoV-2 rS) With Matrix-M Adjuvant in South African Adult Subjects Living Without HIV; and Safety and Immunogenicity in Adults Living With HIV

• 2019nCoV-302; A Phase3, Randomised, Observer-Blinded, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine (SARS-CoV-2 rS) with Matrix-M adjuvant in Adult Participants 18-84 Years of Age in the United Kingdom

• 2019nCoV-301; A phase 3, Randomized, Observer-Blinded, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Immunogenicity of a SARS-COV-2 Recombinant Spike Protein Nanoparticle Vaccine (SARS-COV-2 rS) with Matrix-M Adjuvant in Adult Participants ≥ 18 years with a Pediatric Expansion in Adolescents (12 to < 18 years)

The applicant proposes 5 post-authorisation safety studies including:

• 2019nCoV-402 (UK Post-Authorisation Safety Study Using the Clinical Practice Research Datalink (CPRD)

• 2019nCoV-405 (Global Pregnancy and infant outcomes study using the COVID-19 Vaccines International Pregnancy Exposure Registry (C-VIPER))

• 2019nCoV-404 (US Post-authorization safety study using a claims and/or EHR (Electronic Health Record) database)

• 2019nCoV-401 (EU/EEA Post-authorisation effectiveness study based on a test-negative design using the COVIDRIVE platform)

• 2019nCoV-403 (US Post-authorization effectiveness study using a claims and/or EHR database)

The information included in the SmPC and the PIL is compiled based on the available quality, non-clinical and clinical data, and includes appropriate precautions to be followed by healthcare professionals and patients. Side effects of Nuvaxovid dispersion for injection are continuously monitored and reviewed including all reports of suspected side-effects from patients, their carers, and healthcare professionals.

A RMP and a summary of the pharmacovigilance system have been provided with this application and are satisfactory.

Other information about Nuvaxovid dispersion for injection

A Marketing Authorisation for Nuvaxovid dispersion for injection was granted in Great Britain (GB, consisting of England, Scotland and Wales) on 03 February 2022.

The full PAR for Nuvaxovid dispersion for injection follows this summary.

This summary was last updated in April 2022.

1. Introduction

Based on the review of the data on quality, safety and efficacy, the Medicines and Healthcare products Regulatory Agency (MHRA) considered that the application for Nuvaxovid dispersion for injection COVID-19 Vaccine (recombinant, adjuvanted) (PLGB 54180/0002) could be approved.

The product is approved for the following indication:

Active immunisation to prevent COVID-19 caused by SARS-CoV-2 in individuals 18 years of age and older.

The use of this vaccine should be in accordance with official recommendations.

Name of the active substance is COVID-19 Vaccine (recombinant, adjuvanted).

Nuvaxovid is composed of purified full-length SARS-CoV-2 recombinant spike (S) protein that is stabilised in its prefusion conformation. The addition of the saponin-based Matrix-M adjuvant facilitates activation of the cells of the innate immune system, which enhances the magnitude of the S protein-specific immune response. The two vaccine components elicit B- and T-cell immune responses to the S protein, including neutralising antibodies, which may contribute to protection against COVID-19.

This application was approved under Regulation 50 of The Human Medicines Regulation 2012, as amended (previously Article 8(3) of Directive 2001/83/EC, as amended), a full-dossier application. All clinical data submitted were from studies conducted in accordance with Good Clinical Practice (GCP).

This application was evaluated as part of the rolling review licensing route. The rolling review process is intended to streamline the development of novel medicines. As part of the process the applicant submitted increments of the dossier for pre-assessment by the MHRA, rather than submitting a consolidated full dossier at the end of the product development process.

This product has been authorised as a Conditional Marketing Authorisation (CMA). CMAs are granted in the interest of public health and are intended for medicinal products that fulfil an unmet medical need and the benefit of immediate availability outweighs the risk posed from less comprehensive data than normally required. Unmet medical needs include, for example, treatment or diagnosis of serious and life-threatening diseases where no satisfactory treatment methods are available. CMAs may be granted where comprehensive clinical data is not yet complete, but it is judged that such data will become available soon. Adequate evidence of safety and efficacy to enable the MHRA to conclude that the benefits are greater than the risks is required, and has been provided for Nuvaxovid. The CMA for Nuvaxovid, including the provision of any new information, will be reviewed every year and this report will be updated as necessary.

In line with the legal requirements for children’s medicines, the application included a licensing authority decision on the agreement of a paediatric investigation plan (PIP) MHRA-100149-PIP01-21

At the time of the submission of the application the PIP was not yet completed as some measures were deferred.

The MHRA has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in place for this product at all sites responsible for the manufacture, assembly and batch release of this product.

A Risk Management Plan (RMP) and a summary of the pharmacovigilance system have been provided with this application and are satisfactory.

Advice was sought from the Commission of Human Medicines (CHM) on 28 January 2022 as COVID-19 products are of major public interest.

A national marketing authorisation was granted in Great Britain (GB, consisting of England, Scotland and Wales) on 03 February 2022.

2. Quality aspects

2.1 Introduction

This product consists of a colourless to slightly yellow dispersion for injection presented in a multidose vial. The dispersion is clear to mildly opalescent. One vial contains 10 doses of 0.5 mL. One dose (0.5 mL) contains 5 micrograms of the SARS-CoV-2 spike protein adjuvanted with Matrix-M. Each 0.5 mL dose contains Matrix-M adjuvant consisting of: Fraction-A (42.5 micrograms) and Fraction-C (7.5 micrograms) of Quillaja saponaria Molina extract.

In addition to SARS-CoV-2 spike protein and Matrix-M adjuvant, this product also contains the excipients cholesterol, phosphatidylcholine (including all-rac-α-Tocopherol), potassium dihydrogen phosphate, potassium chloride, disodium hydrogen phosphate dihydrate, disodium hydrogen phosphate heptahydrate, sodium dihydrogen phosphate monohydrate, sodium chloride, polysorbate 80, sodium hydroxide (for adjustment of pH), hydrochloric acid (for adjustment of pH) and water for injections.

The finished product is packaged in a 5 mL vial (type I glass) with a stopper (bromobutyl rubber) and an aluminium overseal with blue plastic flip-off cap. Each vial contains 10 doses of 0.5 mL. Pack size: 10 multidose vials. Satisfactory specifications and Certificates of Analysis have been provided for all packaging components. All primary packaging complies with the current Ph. Eur. quality standards.

2.2 Active substance

rINN: COVID-19 Vaccine (recombinant, adjuvanted)

Structure

The active substance (company code NVX-CoV2373) is the protein product of a recombinant SARS-CoV-2 S-gene encoding the 1260 amino acid spike protein (the full length 1273 amino acid protein minus the signal peptide).

The SARS-CoV-2 viral envelope consists of multimers of the spike (S) glycoprotein which mediate receptor binding and membrane fusion with the host cell. The S gene was codon optimised for expression in Spodoptera frugiperda (Sf9) insect cells from a full-length, prefusion, stabilised SARS-CoV-2 S genetic sequence. A total of five amino acid changes were introduced, including three in the S1/S2 furin cleavage site (RRAR to QQAQ) and two in the HR1 domain where 2 proline substitutions (2P) were inserted at residues K986P and V987P, respectively. It is stated that these mutations were introduced to stabilise the protein. The virus strain name is Wuhan-Hu-1 and was collected from the Wuhan seafood market in December 2019.

Purified recombinant spike (rS) glycoprotein forms trimers which bind with high affinity to the human angiotensin-converting enzyme 2 (hACE2) receptor. The 13 amino acid signal peptide is not present on SARS-CoV-2 rS and thus the rS is 1260 amino acids. The SARS CoV-2 rS protein has 22 known glycosylation sites which results in a heterogenous glycoprotein with a theoretical molecular weight of 163,997 Da.

COVID-19 Vaccine (recombinant, adjuvanted) is not the subject of a European Pharmacopoeia monograph.

Manufacture of the drug substance

The active substance is manufactured, tested and released at Serum Institute of India Pvt. Ltd. (SIIPL). The facilities involved are Serum Institute of India Pvt. Ltd. Hadapsar, Pune - 411028, Maharashtra, India and Serum Institute of India Pvt. Ltd. Manjari BK, Tal -Haveli, Pune-412307, Maharashtra, India. The SIIPL site was inspected by MHRA, UK. GMP certificates or a QP declaration have been provided for all relevant manufacturing sites, testing sites and QP release site. The manufacturer has provided details of the responsibilities of each facility involved in manufacture and testing including responsibilities performed by contract laboratories.

Description of manufacturing process and process controls

The SARS-CoV-2 rS Protein active substance is produced in a Sf9 insect cell line by using a recombinant baculovirus system. A description of the manufacturing process and controls has been provided, including material inputs, critical and non-critical process parameters, and process outputs.

The active substance manufacturing process starts with the revival, expansion and production of the Sf9 cells from the working cell bank (WCB) into shake flasks followed by bioreactor/fermenter using serum-free medium (SFM). The cells are infected by baculovirus inoculum (BVI). The spike proteins are expressed on the surface of the Sf9 cells. At the end of the growth phase, the cells are harvested by centrifugation followed by extraction using a non-ionic detergent low pH treatment, neutralisation and clarification by centrifugation (of neutralised lysate) followed by depth filtration and 0.2 μm filtration. The clarified lysate is subjected to a purification process that includes anion exchange chromatography, nanofiltration and affinity chromatography. The affinity chromatography eluate is subjected to concentration and diafiltration using tangential flow filtration (TFF) and final 0.2 μm filtration to obtain a purified SARS-CoV-2 rS protein active substance.

Control of materials

Raw materials

A listing of the raw materials used in the manufacturing process of the active substance is provided. All the listed raw materials are tested in compliance with their respective monographs. The release specifications of raw materials released based on the supplier certificate of analysis and/or tested with in-house developed specifications are also provided. No raw materials of animal or human origin are used during the manufacturing process of the active substance. There are three materials of biological origin used in the active substance process, namely Insect Cell Media (yeast), Nutrient feed (soy), and Affinity Resin (lentil). Appropriate quality agreements are in place between the applicant and the supplier of the proprietary media and supplements.

Baculovirus

A complete list of raw materials used for the production of the baculovirus vector is presented, including details of the step where it is used, its supplier, source and certificate of analysis. No materials of animal or human origin were used during the manufacturing process of the baculovirus vector or the master virus stock (MVS).

Information about the preparation of the recombinant baculovirus vector is provided, comprising information about the source of the genetic sequence, procedures for the generation of the vector, transfection and preparation of primary virus (P1) and pre-master virus stock (PVS, P2).

The S-protein is a trimeric glycoprotein of 1273 amino acids. The SARS-CoV-2 S glycoprotein wild type (wt) sequence was downloaded from GenBank sequence MN908947 nucleotides 21563-25384. The S gene was codon optimised for high level expression in Sf9 insect cells and biochemically synthesised by Genscript (Piscataway, NJ, USA). Three mutations (RRAR to QQAQ) were made in the S1/S2 furin site of the full-length wt SARS-CoV-2 S protein along with two additional mutations, K986P and V987P, to stabilise the protein as shown in Table 1).

The wild type SARS-CoV-2 S full length S gene was cloned in the pBacSV40 plasmid with a 5’ polyhedron promoter and a 3’ SV40 polyA sequence. The virus strain name is Wuhan-Hu-1. The sequence of the glycoprotein gene was confirmed by DNA sequencing analysis. The pBacSV40 plasmid containing wild type SARS-CoV-2 S with the QQAQ and PP sequence was confirmed by DNA sequencing. Information about the function of the individual structural elements of the plasmid is provided.

Table 1: Sequence change information from wild type for SARS-CoV-2 rS protein

Types of Modifications	Modification
Point Mutation	Lysine 986 -> Proline 986, Valine 987 -> Proline 987
Mutation of Cleavage Sites	Arginine 682 Arginine 683 Arginine 684 Arginine 685 -> Glutamine 682 Glutamine 683 Glutamine 684 Glutamine 685

The plasmid containing the SARS-CoV-2 rS gene was transfected into Sf9 cells using a cationic lipid transfection reagent to produce recombinant baculovirus BV2373. The recombinant baculovirus was plaque-purified, harvested and filtered (P0 virus stock). Detailed descriptions are given for the generation and preparation of the virus stocks. The virus banking system consists of an MVS and WVS. The testing program and results for the MVS and WVS are presented and is in accordance with the relevant Ph. Eur. monographs. Testing includes controls for mycoplasma/spiroplasma, mycobacterium, adventitious agents (NGS), virus titre, sterility and nucleotide sequence analysis.

Cell bank

Sufficient information is provided about the source history and generation of the Sf9 cell substrate. Sf9 cell banks contain cells from the fall armyworm, Spodoptera frugiperda (Lepidoptera; butterflies and moths). Sf9 cells were derived from cells purchased from the American Type Culture Collection (ATCC) that were adapted to grow in suspension culture in serum-free medium. The preparation of the pre-master cell bank, master cell bank (MCB), working cell bank (WCB) and end-of-production cell bank (EOPCB), is described. Testing of the cell banks is in line with ICH Q5A (R1) and ICH Q5D. The cell banks were tested for identity, safety, and purity, and all test results met the acceptance criteria. Testing of cell banks includes controls for sterility, mycoplasma, mycobacterium, spiroplasma, endotoxin, in vitro adventitious agents, in vivo adventitious agents, in vitro assay for bovine virus, karyotype, isoenzyme, Type C particles, retrovirus (reverse transcriptase activity), co-cultivation, product enhanced reverse transcriptase, cell growth, virus replication, PCR assay for detection of specific porcine and bovine viruses. All cell banks have tested negative for viruses, with the exception of the Sf9 Rhabdovirus which is known to be present in Sf9 cells.

Controls of critical steps and intermediates

Critical process parameters (CPPs), in-process controls (IPCs) and critical quality attributes (CQAs) are defined. Appropriate in-process controls and intermediate specifications are applied. The controls (in-process bioburden and endotoxin measurements) used to demonstrate microbial control of the manufacturing process for drug substance are described and found acceptable.

Process validation and/or evaluation

Process characterisation of active substance was performed in parallel with the PPQ campaign at SIIPL as part of a non-traditional approach to enable rapid deployment of a manufacturing process of commercial production, in response to the current global pandemic. The process validation campaign was performed with the equipment intended for the commercial active substance manufacturing process. Additional supportive studies were performed prior to or concurrent to the PPQ campaign to support process validation. These comprised studies on stability of the Sf9 End of Production Cells, WVS hold time studies, buffer biochemical stability studies, process intermediate biochemical stability studies, resin lifetime and re-use studies, residual impurities (including for process-related impurities and residual DNA), viral clearance studies, extractables and leachable risk assessments and filter validation studies. Summaries of these studies are provided. Collectively, the PPQ data overall provides scientific evidence that each stage of the active substance manufacturing process, when executed according to the production batch records, consistently produces an active substance that meets its product specification. However, to further address the assurance of the impurity profile, the applicant has committed to explore possibilities to further optimise the manufacturing process with regard to removal of impurities.

Manufacturing process development

A summary of Novavax’s manufacturing lots used in clinical studies is provided. Lots were manufactured in the US at Emergent BioSolutions, Inc (EBSI) and Fujifilm Diosynth Biotechnologies (FDBU). Lots manufactured and their respective use to date are described. Multiple changes were introduced during active substance process development. Several changes have been introduced which increased product purity. Extensive comparability testing results were provided and discussed in detail. In view of the complexity of the active substance, some variability between batches produced at the different sites may be expected. It is noted that some of the differences are indeed intended (increased purity, different protein and PS80 content). The SIIPL commercial process lots are not considered fully comparable from a quality perspective for potency and binding kinetics when compared with the EBSI/FDBU materials used in the clinical studies. SIIPL active substance batches have higher purity when compared to active substance batches used in preparation of finished product batches applied in phase 2 and phase 3 clinical studies and hence comparability is not demonstrated for this quality attribute. However, these differences can be justified as they are not expected to have an adverse impact on safety or efficacy profiles. This is further supported by the results from clinical study 2019nCoV-101 (two-part phase 1/2 randomised observer blinded study designed to evaluate the safety and immunogenicity of NVX-CoV2373). Although higher frequencies of local and systemic reactogenicity occurred in participants receiving the higher antigen dose (25 μg) compared to the lower antigen dose (5 μg), the safety profile was overall considered acceptable. The proposed upper limit for protein content is significantly lower than the 25 μg/0.5 mL dose used in the phase 1/2 studies. The particle size distribution ranges overall are comparable.

Characterisation

Structural characteristics of the rS protein and particle characteristics have been investigated using a variety of orthogonal methods. The active substance particles consist of rS trimers and PS80 micelles that form a complex. The ACE2-receptor binding domain (RBD) of the spike protein faces outward from a core of PS80 molecules with the rS C-terminal hydrophobic transmembrane region facing toward the micelle interior. This arrangement of multiple rS trimers around a PS80 core is referred to as a rosette. Inter-trimer interactions between rS proteins were also observed resulting in higher order spike multimers. Product-related and process-related impurities have been identified and characterised. Some residual host cell (Sf9) and baculovirus proteins were found to be present in the clinical and commercial batches. Overall, sufficient information on the characterisation of the molecule has been provided. A number of post-authorisation commitments have been agreed with the applicant (recommendations) to provide data to further substantiate this conclusion. Considering the purity levels of the batches used in clinical studies, and the purity levels of commercial process batches, the specification for purity of rS content is acceptable for the conditional marketing authorisation.

Control of drug substance

The active substance specifications include general tests (appearance, pH, PS-80), protein concentration, identity , purity, potency, residual DNA and safety tests (endotoxin, bioburden, mycoplasma/spiroplasma, harvest contamination). The manufacturer has provided adequate justification for these limits, based on efficacy and safety considerations.

Validation of analytical procedure

Validation of the analytical methods used for the control of the drug substance are satisfactory for ensuring compliance with the relevant specifications.

Batch analyses

Batch release results for all batches used in the clinical trials, along with site of manufacture, have been provided and show that all batches conformed to the specifications in force at time of manufacture. Batch analysis data of active substance batches manufactured as SIIPL have been provided. The results are within specifications and confirm consistency of the manufacturing process.

Reference standard

The Reference Standard which is currently used for the potency assay is an intermediate reference standard. This standard was prepared from representative active substance and was calibrated against active substance used in the Phase 3 clinical studies. This provides a link between the reference standard and clinical study material. A protocol has been provided for the calibration of the new primary and working reference standard. After calibration, the new primary reference standard will be bridged against the intermediate reference standard and previous Reference Standard.

Container closure system

The choice of container/closure is adequately described and justified. Stability testing has shown the primary container to be compatible with the drug substance. The primary packaging has been shown to comply with the quality standards of the Ph. Eur.

Stability

The stability data provided are sufficient to support the proposed shelf-life of 9 months for the drug substance stored at < -60°C. The company has committed to continue the stability studies.

2.3 Drug product

Pharmaceutical development

A satisfactory account of the pharmaceutical development has been provided. All excipients comply with either their respective European/national monographs, or a suitable in-house specification. Satisfactory Certificates of Analysis have been provided for all excipients. The finished product composition is described in Table 2 below:

Table 2: Finished product composition

| Name of Ingredient | Function | -|- | SARS-CoV-2-rS | Immunogen/active ingredient | | Disodium hydrogen phosphate heptahydrate ⁴ | Formulation Buffer Agent | | Sodium dihydrogen phosphate monohydrate | Formulation Buffer Agent | | Sodium chloride | Formulation Buffer Agent - Isotonicity adjuster | | Polysorbate 80 | Formulation Buffer Agent - Stabilizer | | Sodium hydroxide | pH Adjustment | | Hydrochloric acid | pH Adjustment | | Water for Injections | Vehicle | | # Matrix-M Adjuvant ² | | | Fraction-A | Adjuvant | | Fraction-C | Adjuvant | | Cholesterol | Formulation Agent | | Phosphatidylcholine ³ | Formulation Agent | | Potassium dihydrogen phosphate | Buffer | | Potassium chloride | Tonicity Agent | | Disodium hydrogen phosphate dihydrate | Formulation Buffer Agent | | Sodium chloride | Formulation Buffer Agent | | Water for Injections | Vehicle | ¹ Nominal concentration

The finished product is formulated on the basis of the total protein concentration of the active substance and a 5% overage is used to compensate for any potential loss during finished product manufacturing.

The vials are filled with a minimum of 6.0 mL to ensure that 10 doses of 0.5 mL can be withdrawn.

Novel excipient - adjuvant

The Matrix-A and Matrix-C adjuvant components contain purified, chromatographic fractions (A and C) of enriched purified bark extract from the tree Quillaja saponaria Molina (saponins) as well as cholesterol from botanical origin, and phosphatidylcholine, from hen’s egg yolk. Matrix-A and Matrix-C are regularly shaped, uniform and stable complexes (nanoparticles) suspended in phosphate buffered saline (PBS). Cholesterol and phosphatidylcholine are present as excipients in the Matrix formulation. Characterisation has been conducted with several orthogonal methods for chromatographic profile, identity, monosaccharide analysis, haemolytic activity, particle size and structure. The impurities related to the manufacture of Matrix-A and C have been adequately discussed. The control specification comprises tests for appearance, identification, concentrations of saponin (SA), cholesterol (CH) and phosphatidylcholine (PC), saponin purity, residual detergent N-Decanoyl-N-methylglucamine, pH, average particle size, ratio CH/SA, ratio PC/SA, bioburden and endotoxins. The specifications and shelf-life will be further reviewed postapproval based on updated characterisation and stability data.

Based on batch release results, results of characterisation tests and the preliminary results of the comparative accelerated stability studies, it is concluded that clinical finished product batches are sufficiently comparable to commercial finished product produced at SIIPL.

This product does not contain or consist of genetically modified organisms (GMO).

Manufacture of the product

A description and flow-chart of the manufacturing method has been provided.

The manufacturing process is described in sufficient detail, including the equipment and materials used, formulation calculations, critical and non-critical process parameters with operating ranges/set points and in-process controls. The process principally involves the preparation of the formulation buffer and active substance, preparation of Matrix-M adjuvant by mixing Matrix-A and Matrix-C, preparation of the co-formulated final bulk, sterile filtration of the co-formulated bulk to the filling machine (isolator), filling into sterilised vials and finishing. All critical steps are adequately controlled. A number of in-process controls are proposed for the manufacturing process and these are considered satisfactory. The PPQ studies confirm that the commercial process performs effectively and is able to produce a finished product meeting its predetermined controls and acceptance criteria.

Finished product specification

The finished product specifications include general tests (appearance, pH, osmolality), protein concentration, identity , potency, content of Matrix-A and -C, safety tests (endotoxin, bioburden), extractable volume and container closure integrity (CCIT). The test methods have been described and adequately validated. Batch data have been provided that comply with the release specifications.

Independent batch testing

Independent batch testing is required for vaccines and provides additional assurance of quality before a batch is made available to the market. Independent batch testing is a function that is undertaken by an Official Medicines Control Laboratory (OMCL). The UKs National Institute for Biological Standards and Control (NIBSC) is responsible for this function. Independent batch testing is product-specific and highly technical: it requires specific materials and documentation from the manufacturer and comprises laboratory-based testing and review of the manufacturer’s test data. If all tests meet the product specifications a certificate of compliance is issued by the OMCL.

Characterisation of impurities

There are no new process related drug product impurities in addition to those described for the drug substance.

Container closure system

The container closure system has been well described and complies with the relevant quality standards of the Ph. Eur.

Stability

Finished product stability studies include batches of the finished product stored in the packaging proposed for marketing. A shelf-life of 9 months at 2-8 °C is accepted based on the supporting data. However, the applicant is required to provide monthly updates for the PPQ lots manufactured at SIIPL using the specified manufacturing process and three PPQ lots manufactured at SIIPL using the commercial scale manufacturing process. This data is required to achieve a comprehensive data package and ensure consistent product quality during shelf-life and is therefore requested as a Specific Obligation.

Suitable post approval stability commitments have been provided to continue stability testing on batches of finished product.

Based on the stability information currently available, a shelf-life of 9 months can be accepted, with the following storage conditions:

• Store in a refrigerator (2°C to 8°C).
• Do not freeze.
• Keep the vials in the outer carton in order to protect from light.

Shelf-life

Unopened vial

9 months at 2°C to 8°C, protected from light.

Unopened Nuvaxovid vaccine has been shown to be stable up to 12 hours at 25°C. Storage at 25°C is not the recommended storage or shipping condition but may guide decisions for use in case of temporary temperature excursions during the 9-month storage at 2°C to 8°C.

Punctured vial

Chemical and physical in-use stability has been demonstrated for 6 hours at 2°C to 25°C from the time of first needle puncture to administration.

From a microbiological point of view, after first opening (first needle puncture), the vaccine should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

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