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Thanks senti, but I was talking about ATLnsiders estimate for Flaskworks potential production capacity based on 10X the capacity of the manual manufacturing method, that may have been in a Flaskworks PR or an article about the system.
Interestingly though, I dug that same PR out not too long ago and reposted it too. And now that you brought it up again, and we have recently discussed this and the TFF potential manufacturing changes during the trial, I have a lingering question about the timing of the change in the trial from phase II to phase III. Do you know when that occurred as it relates to these two significant manufacturing changes? Was it in 2014? Usually, you would not implement manufacturing changes (unless it’s safety related) during one phase of the trial as that could potentially impact the results, so manufacturing changes are normally implemented after one phase has been completed and before another phase is initiated (or before commercialization).
I have thought that if those manufacturing changes were made, it would have occurred in this trial between those phases, and maybe that’s part of the reason why some refer to, and are watching, the last hundred patients or so. This has probably been discussed I’m sure, and I understand one reason is due to the additional 17 treated patients in the treatment arm vs the placebo arm. One question that I’ve had is if one or both of the manufacturing changes were made, along with the sicker patients that were enrolled at the end of the trial, if that is what potentially forced the imbalance of the two arms at the end of the trial. What do you think?
That’s pretty funny ATLnsider, thanks. That phrase has been gaining some traction lately. Maybe it’ll be trending soon . . .
100% senti, a significant portion of that Sawston cold storage will be used for Northwest Bio’s purposes to store tumor tissue and DCVax finished doses. The cold storage can be shared since there’s virtually no risk of cross contamination. You probably know that Advent has an ancillary services agreement with Northwest Bio which is similar the Cognate ancillary agreement which includes: cryopreservation and storage services, shipping, distribution and logistics services, scheduling and software services, documentation and record keeping services, and other miscellaneous services. The logistics companies (CryoPDP/Cryoport, Biolife Solutions) that cell therapy manufacturers and CDMO’s contract with, have also broadened their service offerings to include cold storage, so Advent could potentially use some of that capacity in the more distant future if Sawston capacity is constrained.
ATLnsider, I think there’s many ways to guesstimate the potential production capacity for Flaskworks automation, so until we get more information, it’s really anyone’s guess, and you could be right. Our estimates were really not that far apart using different methods, but that 16,000 number that I threw out was just theoretic, and I wasn’t trying to be accurate at this point because there are too many unknowns. Perhaps my post was a long winded way of saying that I think Sawston is a relatively large facility, with plenty of capacity for Advent to manufacture DCVax for both the UK and EU, and as flipper said, there’s also room for Advent to manufacture for other clients using the high-grade clean rooms, that for the most part, Northwest Bio won’t require. Plus, there’s potentially a way to scale it to the masses when that time comes.
I’ve seen that 10X manual process capacity estimate here before, and to be honest, I don’t know where it came from. Is that taken from Corning’s brochure for the Flaskworks’ MicroDEN system? That it’s supposedly 10X more efficient or something, so somehow it will have 10X the production capacity? I personally don’t think that’s a useful way to analyze Flaskworks potential production capacity because the open manual processes, workflows, and clean room requirements are so different than for the automated, closed processes.
The automated workflow manufacturing process for CAR-T’s is much more similar to the automated workflow process that I think DCVax will have. The first step for both is cell isolation, (with CAR-T’s, the T-cells are separated from the other cells in the leukapheresis material instead of the dendritic cells) and although the CAR-T’s go through an extra process of engineering the T-cells, but the DCVax dendritic cells don’t, otherwise the rest of the manufacturing process involves culturing, washing, filling into dosing containers, and cryopreserving, which is all fairly similar. So, because it's an established autologous cell therapy, that will likely use a similar closed, automated production process as DCVax, it seems (to me) to be a more tangible way to compare and estimate.
To be realistic though, and put these projections into perspective; it’s been almost 5 years since Yescarta was approved, and Kite is still only producing at half of that projected capacity level. Although I anticipate that DCVax will ramp much more quickly than Yescarta, it’s still an expensive, brand-new cell therapy treatment with insurance reimbursement hurdles, complicated logistics, and new hospital protocols to establish, etc., so even though I project that potential capacity, I think the ability to manufacture DCVax in these larger quantities may not be as necessary as rapidly as many here seem to expect.
Agree flipper, manual production will be history, but as I said before, I think there’s a reason that Northwest Bio gives an annual figure for it. And of course cold storage is critical regardless of the manufacturing method. The tumor tissue is shipped and stored in the -20C to -80C range, while the finished doses are cryopreserved and stored in the colder > -194C cryostorage.
I’m not sure if people understand how large the Sawston facility actually is, so I’ll throw some comparability numbers out there. Sawston is roughly double the size of Kite’s 44,000 square foot El Segundo CAR-T manufacturing facility, which Kite estimates is large enough to produce about 4,000 personalized cell therapy treatments annually. The shell size alone shouldn’t be used to compare with potential DCVax manufacturing capability, because this doesn’t account for the difference in manufacturing time or potential space utilization.
It seems reasonable to think that with process optimization using Flaskworks and other automated processes, DCVax-L manufacture time may be reduced from 8 days to 7 days, which is less than half the manufacturing time of Yescarta’s ~16 days. So given that Sawston is double the size and it takes half the time to manufacture DCVax, then theoretically, Sawston should be able to produce 4X Kite’s number, or 16,000 treatments annually using the whole Sawston facility, or the same number of treatments using 1/4 the space. (4,000 treatments using 11,000 square feet) But there’s more.
CAR-T manufacturers use individual all-in-one, end-to-end manufacturing work stations, which isn’t the most efficient use of space, as it ties up each individual work station during the long culturing step. If the Flaskworks system has one culture chamber, then the manufacturing capability would be approximately the same per space utilized. However, with Flaskworks system development, it’s conceivable that, by using larger media fill and waste tanks, and adding additional culture chambers and perfusion pumps, it could produce multiples of that in basically the same footprint. So by adding 10 culture chambers to each system for example, each manufacturing run could produce 10X the number of treatments in basically the same floor space. This might be what Michael Bigger was taking about when he said “cleanroom disruption.”
And sometimes good enough is unacceptable. Anyone who has worked on under-resourced projects knows that when safety and quality can not be compromised, it’s usually the timeline that suffers.
I agree with this post as well. By the way Viking, I’ve read some of your market commentary, and think it’s pretty spot on.
I don’t think Linda Powers is working off a term sheet per se, but she certainly understands how to add value to the company, and I anticipate the following to occur in the next year or so timeframe:
|X| Licensed manufacturing facility
| | Clinical trial data that is approvable by regulators and accepted by medical community as a new standard of care
| | Improved capital structure and listing on major stock exchange
| | Regulatory approval
| | Licensed manufacturing facility for commercial production
| | . . .
I don’t think management is playing games Bob, but I do agree in general, that “independent” boards are mostly a farce, and small shareholders have little say in these matters. The temporary option and warrant suspensions are in place to keep the potential exercises below the number of authorized shares. While some posters seem to think management has a complete disregard for shareholders, I think management is well aware of shareholder angst, and has chosen the least undesirable alternative. Letting the options expire seems unrealistic since there would have been other options like increasing the authorized limit, which would likely not be a popular choice to shareholders who have been kept waiting for clinical trial results, and the other option is a reverse split, which is an even less popular option at this point. It does seem clear to me that the runway is getting pretty short, so one of these other alternatives will have to occur fairly soon. The annual shareholder meeting this year should be pretty interesting.
Right dmb, and Linda Powers said as much at a conference back in 2014 or 2015, and I think mentioned Dendreon as an example of why a CDMO. Advent will likely manufacture for other clients at some point and Sawston will become a multi-product facility, but for the time being, I think the current manufacturing suites will be used exclusively for the compassionate use, manual production of DCVax. Advent won’t begin the next phase of expansion at Sawston until DCVax is ready for commercialization, and there’s sufficient funding. The closed automated systems will likely operate in a much less costly class-C environment, while the current higher class-B manufacturing suites may be shared, and only be utilized for a few manual procedures which have not been automated, like the tumor lysate preparations and quality control testing. The gist of my deleted post was that the sub-lease agreement is far from the raw deal that some allege.
Okay, maybe I was wrong ex. Apparently EVERYONE (except you) knows that there’s one product that Advent will manufacture at Sawston for the foreseeable future, and that product is DCVax for Northwest Biotherapeutics.
The link you posted simply announced that Advent has a customer for their cold storage service.
https://www.adventbio.uk/post/sawston-premises-cleared-for-work-involving-genetically-modified-organisms-class-1-and-2
We are pleased to announce that we have been granted clearance from the HSE for the use of our Sawston premises for work involving genetically modified organisms (Class 1 and 2). The HSE has confirmed that it has no objection to Advent Bioservices performing the notified activity, GM3660/22.1 entitled “Storage of external client GMO material(s) at vapor phase liquid nitrogen (LN2), -20C or at -80C”.
https://www.adventbio.uk/coldstorage
Thanks IkeEsq, that’s good info. I guess you probably know that I was just kidding, but maybe others didn’t. I would never seriously consider doing such a thing.
I coined the phrase “Liau Protocol™” and trademarked it almost 2 years ago. You know hyperopia means far sighted, right? ;) That post may prove to be prescient:
hyperopia
Saturday, June 27, 2020 9:39:42 PM
Re: sentiment_stocks post# 291968
Post# 292166 of 447249 Go
senti, I agree that much will depend on the data, but if it is as good as I think, you may be underestimating not only the total available market, but also the potential annual revenue. I think the brain tumor market alone could be worth over $3B annually.
I believe that Northwest Bio will initially attempt to obtain the broadest label possible, which would include ALL gliomas, both newly diagnosed, AND recurrent. Even if many people here have forgotten that the PEI approved a hospital exemption for DCVax for this broad label, I’m pretty sure that Linda has not. And even if it was initially only able to cover all nd gliomas (which make up over 80% of malignant brain tumors) that would add another 10k to 15k patients to that total available market.
With your numbers, you appear to be estimating the pricing to be around $150k? Is that the wholesale acquisition cost (WAC)? I have thought that Northwest Bio would try to keep the price as low as possible, say between $150k - $200k, but they may have to price it even higher than that to account for discounting and insurance reimbursement. For example, Optune is priced at $22k per month but CMS (Medicare) coverage is only around $13.5k. (40% discounts are common)
Perhaps you were just being conservative, but I’m curious why you think DCVax usage will only be 1/3. I believe (if approved) that usage may be over 2/3 because DCVax will be added to the standard of care for GBM. This was formerly called “the Stupp Protocol” but with DCVax added, I predict that it will become known as “the Liau Protocol.” That has a nice ring to it . . . the Liau Protocol.
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=156569857
Thanks Lykiri, that interview is from the Advanced Therapies Week conference last month, and it’s also on youtube somewhere. While he did talk in general about the importance of data management, his discussion seemed geared toward CAR-T manufacturers and all-in-one work stations.
Have you seen this presentation by Mark Lowdell? It’s a couple years old, but provides a little background on Autolomous and the data management that’s required for the manufacture and supply chain of cell therapies:
https://atmpmanufacture.org/wp-content/uploads/2019/11/autolomous-mark-lowdell.pdf
Haha right Dr B. I hope not either. That looks like Venice, and you definitely wouldn’t want to miss it!
Catchy little ditty senti, thanks
Congrats Dr B. I accepted an early retirement package a few years ago (in my 40’s) and I was going to get another job, but then decided nah. I like traveling too much!
biosectinvestor, it would be a change of the established conditions. I’m not sure what part of the trial you are describing, (actually UCLA has their own version and protocols) however, once there are regulatory approved manufacturing protocols, it would be necessary to conduct a comparability study for a new manufacturing site, and this was done when the trial included Fraunhofer manufacturing.
Again, I’m unaware of the regs you are describing, but they are evolving, and there are some aspects of demonstrating comparability which are unique for cell therapy such as variability and scarcity of cellular source materials. This is why I believe that Advent will use split manufacturing, where a single lot of source material is divided and processed in parallel with both the prechange and postchange processes. This absolutely, can not be done across different labs. There is another method to demonstrate comparability where the post-change process would be compared to historical lots, but this isn’t the preferred method, and obviously wouldn’t be possible at Sawston.
I’ve had this discussion with others who said that the Flaskworks comparability study could be done at Advent’s London lab. It could, but that would require another comparability study to transfer the protocol to another site such as Sawston. This is why NW Bio announced the Flaskworks prototype was delivered to Sawston and the practice runs will be performed at Sawston, because the Flaskworks system will be tested and used at Sawston.
Come to think of it, I posted some links which may be helpful in that post here:
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=167133951
Hehe, sorry biosectinvestor and flipper, that was a comedy of errors caused by my use of future tense instead of past tense when describing the qualification steps, which led flipper to say it was done in March, then my reply saying that it had not been done in March according to the May 12th PR, then you admonishing me . . . anyway, I think we can agree that the qualification steps including the practice runs have certainly been completed by now.
Actually, side-by-side testing does have to be conducted in the same factory. There can be variations between different labs (personnel, equipment, media suppliers) that could have an effect on a product. A comparability study also has to be conducted when a manufacturing site is added or changed.
It was in the May 12, 2021 PR
UK Manufacturing Facility & Phase III Trial Updates From Northwest Biotherapeutics (OTCQB: NWBO)
Application Submitted to MHRA for Certification of Sawston Facility
May 12, 2021, 04:15 ET
In addition to the MHRA submission activities, a prototype of the Flaskworks system has been delivered to the Sawston facility, and the Company currently anticipates that initial practice runs with the system may begin at the Sawston facility during the summer.
https://www.prnewswire.com/news-releases/uk-manufacturing-facility--phase-iii-trial-updates-from-northwest-biotherapeutics-otcqb-nwbo-301289513.html
Yes flipper, that’s what I thought too, but why announce that the prototype arrived in May, and the initial practice runs were expected to start during the summer? When NW Bio events take longer than I expect, I tend to change my original thinking to explain it. And I certainly could be wrong with my timing expectations, it sure wouldn’t be the first time, and it probably won’t be the last.
I’m not saying this would hold up filing a marketing application. Especially if Northwest Bio submits the proposed CP with the application. The regulators expect that there will be commercial manufacturing changes, and timing wise, commercial readiness may coincide with approval.
biosectinvestor, I completely disagree with your characterization of the difference between the manual vs automated culture process, but no point in getting into it.
I should probably clarify though, that I think Advent’s initial evaluation of the Flaskworks device prior to acquisition, was simply for internal validation, and the commercial prototype will go through the qualification process; DQ, IQ, OQ, and PQ, then comparability testing for the regulators. I agree that the FDA does not require human studies for comparability of the Flaskworks system itself, and that Advent may simply do the first minimal qualification of the system. I guess my point was that Flaskworks is only part of a much larger Comparability Protocol, which will take longer to accomplish, and require actual patients to confirm that Advent can achieve the higher commercial specifications and volumes, for the new manufacturing process using the multiple automated systems necessary for commercial production.
thanks for digging that up senti. I watched it again and still love it!
Your wish is granted: The Who - Baba O'riley
There are a number of commercially available automated cell processing systems that could be used for the cell separation step, (remember Flodesign Sonics?) but I’m assuming that Advent will use Northwest Bio’s patented technologies for the two most critical processes.
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=167956196
Haha That's a good one! Thanks for (re)posting.
Hi biosectinvestor, I thought the same last year about testing the original version of the Flaskworks device, however, my thinking has changed as time has passed. I speculate that Advent’s initial testing and validation of the Flaskworks device, which as you say can be conducted with commercially available leukopheresis products, occurred prior to the acquisition. Then, based on Advent’s evaluation and feedback for their commercial requirements, the Flaskworks technical team had nearly a year to develop the clinical device into a prototype commercial system. The May, 2021 PR stated that “a prototype of the Flaskworks system has been delivered to the Sawston facility.” And you’re right, the Flaskworks MicroDEN device was commercially available at the time of the acquisition, so using the word prototype indicates to me that the Flaskworks system delivered to the Sawston facility is probably not that original clinical version.
I’m not suggesting that Advent fitted out the Sawston facility for the automated process using the Flaskworks system. Of course the testing of the Flaskworks system and commercial process development, will be conducted in the research and development labs, while the primary cleanroom space is devoted to compassionate use production. The recent articles about the Sawston facility basically confirmed this: “The facilities include GMP clean rooms for the production of human cell products, research and process development laboratories, and a large cryo-storage facility.”
I’m also not suggesting that dozens of patients will be required, probably only a few. The comparability protocol will pre-specify how many runs will be conducted, and I believe the minimum number required is three. If the results of those tests show inconsistency, then they may have to make adjustments, and run another study, but I doubt they would even begin the study until they were confident that the system was dialed in.
I agree that automating/mechanizing a manual procedure seems pretty straight forward, and what you say may be true with some processes like fill and finish; however, the cell culturing process is far more complex, and changes there can have a far greater impact. For example, did you know that the dendritic cells produced with the MicroDEN system at Northeastern University had different physical characteristics (they were smaller) than cells produced manually in well plates? That alone is a fundamental difference, (does not show comparability) and could indicate other more significant differences. Regulators expect comparability testing to highlight some differences, but it will need to be clearly demonstrated that those differences do not have a negative impact on safety and efficacy, and that the critical quality attributes have not been affected by the manufacturing changes.
Perhaps I exaggerated a bit with words like “phonebook sized” and “monumental,” but it’s an extremely detailed and extensive process to make multiple changes to the manufacturing protocols. The regulatory approved detailed manual process protocols are known as established conditions. Any changes to the established conditions must be reported to the regulators. There’s several categories for these changes; the FDA classifies them as minor, moderate, and major, while the EU/UK use something like type Ia, Ib and II. The addition of a new supplier for media, or re-agents would be considered a minor change, and can be reported in the annual report. However, any process changes to the established conditions are considered major, and each change, must have it’s own detailed risk assessment, and comparability study. Advent can’t simply compare the old manual process final batch releases to the new final batch releases of the new automated process. I’m not aware of any FDA rules which expedite this process as you describe, but I would appreciate any enlightenment.
I appreciate hearing other posters perspectives, there’s really a wealth and wide-range of experience on this board. Sometimes though, I regret making a post because it often requires multiple follow-up posts, which I don’t often have time for. Plus, I’m west of California, so it seems I’m always far behind most conversations.
Thanks biosectinvestor, I’ve seen that first link before and flipper beat me to the reply. I’ve posted links to that Invetech site as well to show what the next version of the Flaskworks device might look like. I agree that there are many different methods and commercial equipment available to perform the manufacturing functions, and that some of Advent’s commercial manufacturing development work likely was completed before Sawston licensing.
I’ve been told that I write in a dogmatic style sometimes and I can’t deny it, but I assure you that I welcome differing opinions and points of view. I was pushing back on the narrative that Flaskworks certification has been completed, which has been repeated multiple times, by multiple posters, but all without plausible explanation, and an understanding of everything that Advent has been working on. Perhaps people confuse the actual comparability study, with the practice runs, which are steps to interface with the Autolomous softtware and sensors, and dial in the Flaskworks system to Northwest Bio’s culturing and maturation protocols, which can be, and likely was, accomplished before licensing.
It is my belief that the Flaskworks comparability study will be a side-by-side comparison, manual culturing method vs automated Flaskworks method, which requires real patients, and that has to be conducted in a licensed GMP facility. The length of time for the actual study will obviously depend on how long it takes to get the compassionate-use patients in the study, and the number of batches required. You don’t want to see much variation between each Flaskworks’ batch, so if there is wide variation, then more will have to be run. At this point it’s really anyones guess how long that will take, but mine is after the second quarter. The second quarter may be the optimistic goal, which is fine, but I don’t have remind anyone about Northwest Bio’s optimistic timelines around here.
dmb, I’m not so sure that I could rank one manufacturing process improvement over another, since closing and automating manual processes make the manufacturing side of the treatment economically and commercially feasible, but if you’re speaking strictly as it only relates to potential increased survival benefit, then I might agree. This might be the other significant improvement that you’re referring to:
NW Bio Receives U.S. Patent On Broad Processes For Producing More Potent Dendritic Cells
Next Generation Technology Already In DCVax®-Direct; Will Be Applicable To All DCVax® Products
BETHESDA, Md., March 18, 2013 /PRNewswire/ -- Northwest Biotherapeutics (NASDAQ: NWBO) (NW Bio), a biotechnology company developing DCVax® personalized immune therapies for solid tumor cancers, announced today that it has been issued a key U.S. patent (#8389278) covering novel processes for manufacturing human dendritic cells. The cells produced through these processes are much more potent in their capacity to activate the immune system than those produced by the standard methods used throughout academia and industry today to produce dendritic cells.
This patent has also been issued in Europe, Japan, Australia, New Zealand, India, China, Korea, Singapore, Russia and other countries.
The standard methods used to produce dendritic cells today involve several key steps, which start with precursors of dendritic cells (called "monocytes") obtained through a blood draw, then develop the precursors into immature dendritic cells, and finally develop these cells into mature and activated dendritic cells. The standard methods cause some premature activation of the precursors before they become immature dendritic cells, and this premature activation orients the cells toward becoming an undesired cell type rather than dendritic cells. This has to be stopped and overcome by treating the cells with a biochemical factor known as IL-4. This redirection results in conflicting signals, and dendritic cells that are somewhat "confused."
In contrast, the patented NW Bio processes closely track the natural processes that occur in a healthy person's immune system. NW Bio's methods avoid the premature activation of the precursors (monocytes), and develop pure immature dendritic cells -- avoiding the conflicting and confusing signals, and the need to override those signals with IL-4.
Building upon the pure immature dendritic cells, NW Bio's patented methods develop mature and activated dendritic cells that are far more potent than dendritic cells produced in the standard way. For example, NW Bio's dendritic cells produce as much as 10X or more the amount of signaling compounds which are key to mobilizing other active agents of the immune system, such as T cells (which infiltrate and attack tumors) and B cells (which produce antibodies).
NW Bio is already using these next generation methods for producing more potent dendritic cells in its production of DCVax-Direct. The same patented methods for activating dendritic cells were also used in the pre-clinical animal studies with DCVax-Direct. In those studies, injection of these potent dendritic cells into some of the tumors in each of the animals resulted in complete clearance of all tumors (both the tumors injected with DCVax-Direct and the tumors not injected) in 80-100% of the animals in the various studies, indicating a system-wide immune response.
Going forward, NW Bio's now patented methods of producing more potent dendritic cells will also enable development of the next generation of NW Bio's other two product lines: DCVax-L and DCVax-Prostate. The current DCVax-L and DCVax-Prostate products have already delivered striking results in clinical trials to date, extending the time to tumor recurrence and the patients' survival time by 1-1/2 to 2 years or more, with a substantial portion of patients going far beyond that. Incorporating NW Bio's patented methods for more potent dendritic cells will enable production of enhanced versions of these DCVax-L and DCVax-Prostate products.
"We are pleased to add this important U.S. patent to our large portfolio of intellectual property, with 17 patent families comprising over 180 issued and pending patents worldwide," commented Linda F. Powers, CEO of NW Bio. "Our strong IP position complements and protects our leading operational position in the immune therapy space, with two product lines already at the Phase III stage, and a third product line at the Phase I/II trial stage, and with operations and manufacturing established in both the U.S. and Europe."
Dr. Marnix Bosch, Chief Technical Officer of NW Bio, commented: "Our patented manufacturing process is an important advancement and quite different from the methods now being used by parties around the world. The significant increase it produces in dendritic cell potency helps place NW Bio at the cutting edge of next generation immune therapies."
https://www.prnewswire.com/news-releases/nw-bio-receives-us-patent-on-broad-processes-for-producing-more-potent-dendritic-cells-198760831.html
I didn’t know those details senti, but TFF can certainly be used for DCVax-L. Whether they actually validated the system back then, or Advent is doing it now, shouldn’t really matter in the big picture, but if it was previously validated, then obviously that would be one less task for Advent now. I simply assumed that TFF will be used because I think that Linda Powers wants to control the manufacturing process using NW Bio’s patented systems, as much as possible.
Thanks flipper, I don’t recall that a filter was part of the (MicroDEN) device, (and that seems like a detail that I would remember) but it has been a couple of years since I looked at the patent, and the Northeastern University paper. As I recall, step one was seeding the (already isolated) monocytes into the two culture chambers, where they are perfused with differentiation media. I know for DCVax-Direct, it’s all enclosed in one device, so I have thought that in the development of the Flaskworks’ commercial system, TFF would be incorporated eventually.
You make a very good point though. It’s probably better to look at the patents. I have thought of the two Flaskworks’ systems by the commercial names MicroDEN and BATON, and separated the technologies of each. The filter you describe may be a part of the BATON - I haven’t taken a deep dive on that system. After one of our previous exchanges, you got me thinking about the possibilities of combining the different elements of each system into a commercial system for each DCVax product. I hope that the brilliant Shashi Murthy and the technical staff that came with the Flaskworks acquisition, and Dr. Bosch, are way ahead of us on that.
Wasn’t it Donald Rumsfeld who said “you go to market with the manufacturing system that you have, not the one that you want,” or something like that. One of the questions that I’ve had is: how many resources have been directed toward the development work for this first commercial system? Are they still small, benchtop machines that must be put in incubators to control temperature and CO2 levels, or has this been enclosed in a larger cabinet where environment conditions can be controlled? Does it simply have in-process sensors and need to be adjusted by a technician, or has controlling that process also been automated? Are there multiple culture chambers or only one? Has TFF been incorporated? (I could go on)
I submitted a number of questions about Flaskworks for the annual shareholder meeting last year, but none were answered. I’m sure we’ll get some answers at the next one though.
Thanks for the comments dmb2. I used the Finia system as an example because it’s compatible with cryovials that are used in Northwest Bio’s protocols. Most of the smaller scale fill and finish systems are geared toward CAR-T manufacturers who use single-dose cryobags, like that example.
senti, I missed those conversations, but it doesn’t surprise me that this has been discussed before, or that there were naysayers suggesting that it couldn’t be used for DCVax-L.
I don’t know if it was actually validated for DCVax-L, but the patent was announced close the the mid-point of enrollment of the DCVax-L trial. I think it was originally designed during the manufacturing development work for DCVax-Direct, and it was obviously used in the production of DCVax-Direct for that clinical trial, but it was FDA approved, and I have always assumed that it could also be used for DCVax-L, partly because NW Bio said it could be used in DCVax trials, and products.
Tangential flow filtration is a common method to isolate or separate cells. It uses pressure and counter flow to push the desired or undesired cells through ultrafiltration membranes with highly defined pores. The system that Northwest Bio has patented, is a self-contained, closed automated system that separates the desired monocytes (precursors to dendritic cells) from the undesired blood constituents like lymphocytes, erythrocytes, platelets etc., from the patient’s leukapheresis material. This is the first step in the manufacturing process for both DCVax-L and DCVax-Direct. The system has disposable sets where I assume the monocytes are collected so they can be transferred to the next process step. (culturing)
There are a number of commercially available automated cell processing systems that could be used for the cell separation step, (remember Flodesign Sonics?) but I’m assuming that Advent will use Northwest Bio’s patented technologies for the two most critical processes.
NW Bio's Patent Portfolio Further Expanded With Manufacturing Automation Patent
BETHESDA, Md., Sept. 10, 2013 /PRNewswire/ -- Northwest Biotherapeutics (NASDAQ: NWBO) (NW Bio), a biotechnology company developing DCVax® personalized immune therapies for solid tumor cancers, announced today that it has been issued another key U.S. patent (#8,518,636) covering a next generation process for manufacturing lower cost human dendritic cells of both a higher quality and higher reliability.
This next generation system has already been cleared by FDA for use in the manufacturing for NW Bio's clinical trials. These systems are now in use producing the vaccines which already have been injected into the tumors of DCVax-Direct patients.
This next generation process automates certain crucial stages of the manufacturing process within a self-contained system. Automating some or all of the production process within such a system can eliminate the need for today's extremely expensive "GMP" clean rooms (with, for example, special air handling to maintain sterile air in an entire building). Eliminating the special costs for such clean rooms will further enhance product economics, allowing wider margins and pricing flexibility.
At the heart of this next generation manufacturing advance are Tangential Flow Filtration machines, or TFF for short. These machines and associated disposable sets provide an automated, closed system for the crucial stages of the manufacturing process isolating the particular immune cells that become the dendritic cells in the Company's DCVax products.
Most significantly, the dendritic cells produced through this next generation system, are manufactured using procedures which are more closely related to what one finds in nature. The result is increased potency of the dendritic cells (which are the active agent in the DCVax products).
As such, full implementation of the TFF can be another major step forward in advancing immune therapies, and help to position the manufacturing of DCVax products for potential commercial scale-up when the time comes.
"Ongoing development of our technologies for cost reduction and simultaneous enhancements in quality continues to strengthen our competitive position," commented Linda Powers, CEO of NW Bio. "The TFF system provides major advantages in this regard, and the issuance of this latest patent is a significant addition to our portfolio of over 180 issued and pending patents worldwide."
Dr. Marnix Bosch, one of the inventors on this line of patents, says: "We have approached the issues of dendritic cell manufacturing from a process-improvement perspective, and the material covered in these issued patents takes advantage of the natural biology of dendritic cells and their precursors, thereby allowing us to produce more potent dendritic cells in a more efficient and automated system."
https://www.prnewswire.com/news-releases/nw-bios-patent-portfolio-further-expanded-with-manufacturing-automation-patent-223111161.html
Ha right. I won’t hold my breath. Did you know that Kite invited investors to the grand opening of their state-of-the-art CAR-T manufacturing plant in El Segundo back in 2016? It was a pretty big deal at the time since no cell therapy (besides Provenge) had yet been approved. Lots of Michael Bigger types and biotech analysts were asking detailed, sophisticated questions, but the Kite reps were pretty tight lipped and didn’t reveal much there, or on the tour. Some pretty good discussions among the investors and analysts though.
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.
ski, the requirements for the marketing applications, applicant information, pre-clinical studies, clinical studies, product/manufacturing information, and labeling (the Common Technical Documents) are essentially the same in both jurisdictions, but the UK seems more willing to make exceptions and cut through the bureaucracy for approval, under certain circumstances, to speed an innovative treatment to patients with unmet medical needs. Maybe there’s less political and Big Pharma influence on the regulatory process and insurance reimbursement in the UK.
So now that Northwest Bio has an approved GMP facility in the UK with the ability to produce DCVax (in limited quantities), and since DCVAx meets the criterial for some of the new accelerated pathways in the UK, and holds a Promising Innovative Medicine designation by the MHRA, it makes sense (to me at least) to seek a marketing approval in the UK first.
Huh? Flaskworks certified? Seriously? You’re using the words of wordsmiths to deduce this? Can you please explain how this was accomplished?
Thanks Lykiri for the new Linda Liau presentation. Your DD is unmatched, and much appreciated.
It looks like the same information that she presented last summer. Is there anything new or different here?
Interesting flipper, I talked to someone from Northwest Bio about a year ago, and he said they were all very excited about the new approval pathways in the UK. I mentioned the 150-day assessment and the rolling review and he said “yes, those . . . aaaand others.”
It wouldn’t surprise me if Northwest Bio attempts one of these pathways:
Conditional Marketing Authorization Applications
The MHRA has introduced a national conditional marketing authorization (CMA) scheme for new medicinal products in UK effective from 1 January 2021. e eligibility criteria for this scheme, as that of the EU scheme, is intended for medicinal products that fill an unmet medical need and for serious and life-threatening diseases where no satisfactory treatment methods are available, or where the product offers a major therapeutic advantage.
The MHRA determines eligibility for a CMA at the time of MAA assessment. The MHRA does not have a specific application route for a CMA. e sponsor needs to file the MAA dossier for a full marketing authorization. At the completion of the MAA dossier assessment, the MHRA will determine whether to approve the application and grant a conditional MA or whether the benefit-risk ratio is negative and reject the application. e CMA may be granted where comprehensive clinical data is not yet complete and available. e sponsor must provide justification for a CMA, including the ongoing clinical studies’ status and timing of the availability of comprehensive clinical data. CMAs are valid for one year and can be renewed annually
Exceptional Circumstances Marketing Authorizations
From 1 January 2021, the MHRA’s existing scheme for applications under exceptional circumstances will continue to be available for medicines where a comprehensive data package cannot be provided because the condition to be treated is rare or because the collection of full information is not possible or is unethical. This scheme has the same eligibility criteria as the EU scheme (see Chapter 2). e designation of a product as being eligible for an exceptional circumstances scheme by EMA or another jurisdiction may be taken into account by the MHRA, but the final decision on eligibility of the product for the GB scheme will rest with MHRA.
Orphan Medicine Designation, Orphan Medicine Development/ Marketing Authorization Application
In the UK, no premarketing authorization orphan designation process exists, and if a medicinal product has been designated an orphan in the EU under Regulation (EC) 141/2000, an MAA can be submitted for the orphan medicine designation under regulation 50G of the Human Medicines Regulation 2012 (as amended). An orphan medicine designation application and the associated MAA (submitted together) in the UK can only be considered in the absence of an active EU orphan medicine designation.
The orphan designation criteria mirror those in the EU. Medicines need to fulfill the following criteria to qualify for orphan designation in an orphan condition:
* It must be intended for the treatment, prevention, or diagnosis of a disease that is life-threatening or chronically debilitating.
*the prevalence of the condition in the UK must not be more than five in 10,000, or it must be unlikely that marketing of the medicine would generate sufficient returns to justify the investment needed for its development.
* No satisfactory method of diagnosis, prevention, or treatment of the condition concerned exists in the UK, or, if such a method exists, the medicine must be of significant bene t to those affected by the condition.
* Satisfactory methods may include authorized medicinal products, medical devices, or other methods of diagnosis, prevention, or treatment used in the UK.
To obtain the designation, the sponsor needs to submit an orphan medicine designation application form along with the MAA. e MHRA makes the decision on orphan status at the time it decides whether to approve the marketing application.
This approach differs from EMA, which includes a process for granting the orphan medicine designation in advance of the MAA submission and offers orphan fee incentives and other benefits for sponsors of orphan medicines during development. The MHRA’s advisory committee, the Commission on Human Medicines (CHM), will examine the application for orphan designation concurrently with the MAA under review. Medicines with an orphan marketing authorization will be listed on the UK Orphan Register.
In the UK, no orphan designation is issued separately from the MA. Therefore, if a change of ownership application is submitted, the orphan designation will automatically transfer to the new marketing authorization holder.
It is assumed that the MAA requirements for approval will be similar to EU requirements. ere might be a risk if the MHRA requirements differ, and additional work or evaluation of a new parameter during development is requested. Also, there may be difficulties navigating differences between MHRA and EMA opinions on protocol design or development plans.
Scope of Orphan Medicine Exclusive Approval
Once a medicinal product receives MA with orphan designation in the UK, it benefits from 10 years of market exclusivity. e market exclusivity period begins on the date of the first approval of the product.
The UK also will recognize remaining market exclusivity for centrally authorized medicines (granted prior to 1 January 2021) in the EU that are converted to UK marketing authorizations. Unlike the EU, it is not necessary to submit orphan maintenance reports to the MHRA, but they can be submitted as additional information.
Market Access
The following three Health Technology Assessment (HTA) agencies have adopted special assessment criteria for orphan medicinal products (OMPs) in the UK:
1. The National Institute for Health and Care Excellence (NICE) includes a program for ultra-orphan medicine (highly specialized technologies [HST]).
2. The Scottish Medicine Consortium (SMC) includes orphan and ultra-orphan modi er criteria.
3. The Welsh agency, All Wales Medicines Strategy Group (AWMSG), includes additional criteria to consider the severity and unmet need.
A nominative prescription of the OMP from a National Health Service (NHS) doctor automatically provides the right to reimbursement to the patient.
https://www.raps.org/RAPS/media/Publications-Resources/Sample-Chapter/Orphan-Drug-Development-for-Rare-Diseases-Sample-Chapter.pdf
Thanks Basin. This is a very significant milestone achievement, and I’m glad it was announced. Start the clock . . .
Viking, cell therapy and its manufacturing is in its infancy so I would agree with your friend that yes, over time, cell therapy treatments will likely be produced in specialized hospital labs. The first version of the Flaskworks’ system is only capable of automating part of the manufacturing process, (culturing, maturation, lysate pulsing, and washing) but there’s several other steps in the manufacturing process that currently require highly skilled technicians and expensive cleanrooms. I believe that Advent is developing an automated workflow using multiple pieces of equipment to close and automate most of these processes for the commercial production of DCVax, but it will be many years down the road before DCVax can be manufactured in hospital labs using the Flaskworks’ system. I think the plan is to follow the established central manufacturing model of the CAR-T’s, and have regional manufacturing facilities while manufacturing is further developed and optimized.
There are other completely closed and automated cell therapy manufacturing systems that are capable of manufacturing cell therapies start to finish like the CliniMACS Prodigy, Cocoon, and Cell Shuttle that I think are likely to be used in a hospital setting far earlier than Flaskworks. I answered a similar question a while ago and provided links to some of these more advanced systems here
Thanks ATLnsider, nothing really new but good publicity.
Agree senti, Advent Bioservices’ price list for “Specials” treatment in the UK, that TiltMyBrain posted on Twitter a while back, confirms an extended payment schedule. I believe the commercial price and payment schedule will be similar, despite a significantly lower automated cost of production using the Flaskworks’ system.
$NWBO looks like Advent is getting ready to ramp up production at Sawton pic.twitter.com/pqpjVZnVLr
— TiltMyBrain (@TiltMyBrain) April 16, 2021