Documento de la EMA sobre la vacuna:
https://www.ema.europa.eu/en/documents/assessment-report/nuvaxovid-epar-public-assessment-report_en.pdfLuego copio un resumen de nibbana de IV centrado en el producto y las validaciones.
Me lo he leído y es correcto, pero se deja que hay varias validaciones y ensayos que no están completados y que la empresa tiene que hacer antes de determinados plazos. En general dan por bueno lo presentado pero todo es gracias a tener las fases 3 con productos fabricados en sitios distintos que han dado tan buen resultado...
El proceso de SII es algo mejor y los lotes son más puros. Por lo leído, creo que los de Político, sin tratar la información de forma justa porque tenían intenciones aviesas, disponían de información correcta y que la FDA no estaba convencida del todo de lo que la empresa le presentaba. Había un problema de purificación/demostración de la misma. Y aún no está completado del todo, pero parece suficientemente válido o demostrado que es buena y funciona.
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PPQ
Process validation and/or evaluation A stepwise strategy for defining and validating the manufacturing process of the active substance produced at SIIPL through the process life cycle, i.e. stage 1 - process design, stage 2 - process qualification, stage 3 - continued process verification following process performance qualification (PPQ) throughout the commercial life cycle of the product)
Manufacturers
FDBU: Fujifilm Diosynth Biotechnologies United States
EBSI: EBSI Emergent BioSolutions, Inc
SII: Serum Institute
Different vaccine versions:
EBSI
2019nCoV-101 (pre-PPQ clinical material)
2019nCoV-302 (pre-PPQ clinical material)
FDBU
pre-PPQ (clinical material)
PPQ
SII
PPQ
Phase 2 (AU/US) Vaccines Used
EBSI 2019nCoV-101
FDBU pre-PPQ
Phase 3 Vaccines Used
EBSI 2019nCoV-302 (Phase 3 UK)
FDBU pre-PPQ (Phase 3 US/MX)
Novavax's strategy was to demonstrate comparability between:
1) EBSI and FDBU (Both 2019nCoV-101 and 2019nCoV-301)
2) FDBU pre-PPQ and PPQ
3) FDBU PPQ and SIIPL
Purity
is expressed as %rS and %gp64 is tested by peptide mapping/mass spectrometry (MS) and is considered indicative of an overall higher gp64 content in the FDBU lots when compared to EBSI lots.
Impurity:
FDBU: predominant impurity is gp64
EBSI: predominant impurity is Sf9 protein
SDS-PAGE method is used for release
The Gen1v2 potency assay specifically measures binding of hACE2 receptor dimers to protomers within the rS trimers and is considered the key functional assay to ensure proper folding of rS and integrity of the receptor binding domain.
Specification for purity of rS
Considering the purity levels of the batches used in clinical studies, and the purity levels of SIIPL batches, the specification for purity of rS content is acceptable.
Results:
The purity data for EBSI batches are not directly comparable with FDBU and SIIPL batches as different methods have been used.
SII PPQ vs FDBU pre-PPQ
"SIIPL 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"
SII PPQ vs FDBU PPQ
When considering all protein impurities, and not only gp64, SIIPL batches do seem more pure than FDBU (and EBSI), both by peptide mapping/MS and SDS-PAGE.
The most notable difference in the results for various lots is the higher potency (as tested by hACE2 receptor binding ELISA) and faster binding kinetics association rates for the SIIPL lots compared to the FDBU lots.
Novavax says:
1) "the slight increase in active substance potency is not likely to affect the efficacy of the vaccine"
2) "considers that minor differences observed in the ka (association/binding) rate for different active substance lots produced at different sites are most likely due to the assay variability and not due to differences in the quality of the active substance."
FDBU
An acceptable safety profile has been shown for the FDBU batches tested in clinical studies. These batches are considered worst-case with respect to impurity levels, compared to commercial batches. // Still P2/3 results were great
The totality of the data demonstrates overall comparability of the materials manufactured at FDBU prior to PPQ and the materials produced for PPQ.
On average, the PPQ lots from both FDBU and SIIPL manufacturing sites are considered comparable
Acceptance Criteria:
Active substance batches manufactured at FDBU and at SIIPL have been retested with the improved assay, using the same reference standard and thereby allowing a comparison between the potency results of FDBU and SIIPL batches. The potency of SIIPL batches were higher than the potency of FDBU batches, possibly caused by the higher purity of SIIPL batches. Potency results of batches of both manufacturers have been used to establish the acceptance criteria which is considered acceptable.
Stability:
FDBU active substance lots remain within specification after 9 months when stored at long-term conditions (-70ºC ± 10ºC). No significant changes in purity (SDS-PAGE) are discernible under these conditions.
Limited stability data is available for the PPQ lots produced at the commercial site, SIIPL.
New Sites Requirements:
3-way comparability for the active substance will be performed, comparing the active substance from the new facility to material both from SIIPL and the clinical manufacturing site FDBU.
Sounds like:
SII has the best version; then
FDBU PPQ; then
FDBU pre-PPQ (aka clinical trial version), which is the lowest bar but still showed great P2/3 safety/efficacy
New manufacturing sites have to compare the vaccine produced at the site with the FDBU version and SII. Which probably means FDBU is also good to go.
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Y ahora uno de BillyT con el que estoy de acuerdo:
My concern is that the FDA is not going to be as receptive as CHMP to some of the items identified in the report. We already know approval in Canada and Australia has been delayed due to questions raised by regulators. I suspect FDA is going to have similar questions upon review of the CMC filing. Betting that FDA is going to rubber stamp the package because it was approved by EMA is not a wise bet. None of the Phase 3 trials were run in the EU and they are not Country of Origin.
That said, I don’t think all hope is lost. If the FDA reaches the same conclusion that the SII produced vaccine is as good or better than the FujiFilm vaccine, the package should be acceptable. The issue is the standard this package sets for FujiFilm, and how long it might take Novavax to get FujiFilm up to the same purity levels. Like I said, I have heard that the problem has been resolved, but we have not seen the end result of a supplemental filing. Let’s hope Erck has some good news on that front on Monday.
I also want to read through the report some more this weekend to see if there are any more useful nuggets to be gleaned. On first read it sounds like Novavax has promised to make some changes in their testing going forward.
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Estoy convencido que han tardado tanto porque hay algunos aspectos que EMA ha aceptado que la FDA no iba a aceptar sin estar Fuji como esperaba. Y lo que han hecho es ganar tiempo para tenerlo listo. Si veis el el informe de la EMA, hay un par de cosas urgentes que solventar (una fundamental y que imagino es la que la FDA ha dado guerra con ella; y ojo que hasta mitad de año quizás no va a estar lista). Página 162:
In order to ensure consistent quality over the product life cycle, the MAH should adequately bridge the reference standards and review the finished product potency limits when additional data become available. Antes del 31 julio de 2022.
Además, hay 52 recomendaciones que la empresa tiene que completar, a partir de la página 163. Todo ello está explicado en detalle en el documento.
