NorthWest Biotherapeutics Inc (NWBO)

[hyperopia]

Is NWBO capable of submitting and perhaps clearing MAA with manual production method in UK, and if not, when would automated need to be validated before commercial approval? Could it happen during the MAA review period? ?

Yes, of course Northwest Bio can submit a MAA using their current manual production method. Whether the MHRA would approve it, is debatable. The MHRA has approved DCVax-L for compassionate use based on the manual production method, but the GMP requirements for an investigational product are not the same GMP for a commercial product. I’m not sure if you saw another post I made about this:

"Each clinical or investigational batch can vary widely depending on the skill of the technician or other factors, but commercial manufacturing requires far more consistency and reliability. Each stage in the commercial manufacturing process must be characterized and fully validated, which builds quality into the final product. The FDA defines process validation as, “…the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product”. Investigational products do not require process validation, and only require end-product testing. There will also be different requirements for cleaning, packaging, distribution, and documentation, etc., for a commercial product.

After Northwest Bio applies for an MAA, the MHRA will still need to conduct another inspection of Sawston to insure that Advent’s Quality Management Systems are designed to meet the challenges, and comply with the principles of Good Manufacturing Practice for a commercial product."

The ASCO presentation confirmed that Advent is translating the manual processes to automated processes, and this major (type II) change requires a change management/comparability protocol, and process validation data which is normally submitted in the manufacturing module of the MAA/BLA, but yes, this data and analysis could be submitted subsequently in a post-approval supplement when it’s completed. Generally, the comparability/change management protocol is submitted to the regulators before the comparability testing begins for their approval/feedback, and it can be included in the MAA as a preemptive measure to assure regulators that additional manufacturing development studies are on-going and will be concluded prior to commercialization.

There’s a new accelerated pathway in the UK that seem particularly advantageous for Northwest Bio, since the complete manufacturing data won’t be available when the initial submission begins. The Rolling review pathway allows the applicant to submit the application in separate parts, and each module is assessed when submitted.

Rolling review for marketing authorisation applications
Use the rolling review route when you want to submit your eCTD dossier in separate parts for pre-assessment instead of making a full consolidated document submission.

The rolling review is a new route for marketing authorisation applications (MAA), where an applicant for a marketing authorisation submits modules of the eCTD dossier incrementally for pre-assessment by the MHRA rather than as part of a consolidated full dossier submission.

The rolling review is intended to streamline the development of novel medicines by offering periodic enhanced regulatory interaction and advice to reduce the risk of failure at the final phase and may be integrated with the Target Development Profile (TDP) to provide a clearer pathway for development of innovative medicines.

Eligibility
Rolling review can be used for a new active substance (NAS) in the UK, Great Britain (England, Scotland and Wales), or Northern Ireland. This is in accordance with regulation 50(5) of the Human Medicines Regulations, or for a similar biological medicinal product in Great Britain in accordance with regulations 53A of the Human Medicines Regulations.

MAAs for any NAS based on a ‘full dossier’ are eligible for the rolling review. Biosimilar applications are also eligible for inclusion in the scheme.

How to apply
The process is a modular approach to submission and evaluation. The quality, non-clinical and clinical data may be submitted separately or jointly, depending on individual circumstances and/or data availability, in the format of common technical modules CTD modules 3-5.

https://www.gov.uk/guidance/rolling-review-for-marketing-authorisation-applications

Guideline on process validation for the manufacture of biotechnology-derived active substances and data to be provided in the regulatory submission
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-process-validation-manufacture-biotechnology-derived-active-substances-data-be-provided_en.pdf

Questions and answers on post approval change management protocols
https://www.ema.europa.eu/en/documents/scientific-guideline/questions-answers-post-approval-change-management-protocols_en.pdf

Comparability considerations for Advanced Therapy Medicinal Products (ATMP)
https://www.ema.europa.eu/en/documents/other/questions-answers-comparability-considerations-advanced-therapy-medicinal-products-atmp_en.pdf