NorthWest Biotherapeutics Inc (NWBO)

[hyperopia]

There’s a lot of focus on the validation of the Flaslworks system, which is certainly a critical piece of equipment and where the cells spend 90% of the manufacturing time, but as the saying goes, “the process is the product.” What the regulators will actually be approving is an entirely new commercial process, which incorporates the new automated equipment. The Flaskworks bioequivalence study is part of a larger (phonebook sized) Comparability Protocol (CP) which is a detailed plan for assessing the risks and effects of the proposed manufacturing change(s) on the identity, purity, potency, and quality of a product. The comparability protocol likely took months to prepare and was probably submitted to a regulator to incorporate their feedback on the proposed changes and assessment methods. The CP can be preemptively submitted in the CMC section of the original MAA or BLA, while the results and data analysis can be submitted later when completed in a post approval supplement. Or the MAA or BLA can be submitted based on the manufacturing method of the clinical trials, and the entire Post Approval Change Management Protocol (PACMP) with data analysis, can be submitted separately later, as a post approval supplement.

I believe that Advent has developed an automated (digitized) workflow using multiple pieces of equipment to close and automate most of these processes for the commercial production of DCVax. The lot release specifications required for a commercial product are much more stringent than for clinical trials, so it’s necessary to eliminate technician variability, and contamination risk by closing and automating the open manual processes. (recall that Novartis was forced to give away over 25% of Kymriah batches for free because they could not meet commercial specs) Part of process optimization also involves reducing high cleanroom and labor costs, and eliminating potential time-sensitive bottlenecks due to manual processes. (there’s no sense in automating and speeding up certain processes, only to be backed up later by a lengthy manual step following it)

I believe the first manufacturing step, isolation/enrichment of PBMC’s from the leukapheresis material, has already been closed and automated with Tangential Flow Filtration, and the culturing, maturation, lysate pulsing,and washing will be automated and closed within the Flaskworks system. The final, “fill and finish” step is currently open and manual, which brings inherent technician-dependent variability, potential contamination risk, high labor and cleanroom costs, and a potential bottleneck in higher volumes, so I believe it will also be closed and automated for commercial production. I’m guessing that Advent may use a commercially available fill and finish system like the “Finia,” which is capable of filling individual doses into cryovials. Although it shows cryobags instead of vials, there’s a video which compares this automated system to the manual method here

Advent has been working on a monumental task that not only includes building out and certifying Sawston, but also developing a new automated manufacturing protocol based on the previous manual protocols, and incorporating that with Autolomous’s manufacturing execution system (MES,) a comprehensive, dynamic software system that monitors, tracks, documents, and controls the process of manufacturing goods from raw materials to finished products. Some of this work has been done, but a good part could not even begin until production was started at Sawson, so anyone who thinks this will be completed by the first or second quarter is probably underestimating the task.