Will Prodigy change everything?

by Alexey Bersenev on August 6, 2016 · 6 comments

in cell product, cell separation

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In the last decade advanced cell therapies are becoming highly commercialized. Industry developers, in general, favor so-called centralized model of cell product manufacturing/ delivery. In centralized model, one big manufacturing plant produces and delivers many many (thousands) products within a country or internationally. In the last few years, Biotech and cell therapy companies (Novartis, Kite Pharma, UniQure…) heavily invested in development of centralized facilities. In the other camp, academics, physicians and tools manufacturers are betting on decentralized or “point-of-care” model of cell therapy manufacturing/ delivery. You can read more about pros and cons of each model in the recent reviews – here and here. But I’d like to focus today on potential catalyst for shifting from centralized to decentralized model.

Proponents of decentralized model of cell therapy delivery would like to use relatively simple/ user-friendly, automated, closed system-based device, which can do many manufacturing processes at once. We call this type of devices “all-in-one”. Of course, “all” is not equal 100% , but combining many major processes, which are usually described in bioprocessing as separate “unit of operations”. Three years ago, German company Miltenyi Biotec has launched new device CliniMACS Prodigy (CE mark in Europe). I’d consider Prodigy’s launch as the first attempt to introduce a prototype of “all-in-one” device to clinical cell therapy world. Unlike previous generation of devices with capability to do more than one process, Prodigy went as far as integration of cell separation, magnetic cell sorting and cell culture.

Since launch, seem like Prodigy is doing well on the market (as much as I can say from attending conferences). Prodigy clinical validation reports are available now for CAR T-cells, mononuclear cells from bone marrow and peripheral blood, CD34 cell selection, NK cells and virus-specific T-cells. The main advantage of Prodigy, of course, is process integration capability. Importantly, it is fully automated, closed system device, which can save a lot on time and labor. I’d like to highlight few disadvantages of Prodigy:

  • capability to produce only one batch at time (1 patients –> 1 device)
  • high complexity and absence of backup device (equal alternative) underlies high risk
  • low flexibility of cell incubation unit (limited volume/ cell concentration)
  • relatively high cost.

Now, I’d like to discuss the main potential impact of Prodigy and devices alike. I think, Prodigy could be a catalyst for shifting from currently widely accepted centralized model to “point-of-care” model of cell manufacturing/ delivery. Devices like Prodigy is exactly what most proponents of decentralized manufacturing model were dreaming about. It could, potentially, “democratize cell therapy” by making clean room facilities obsolete and simplifying whole manufacturing process by pushing few buttons and hanging the bags. Single use disposable of multifunctional device is a replacement of class 10,000 clean rooms. Full automation is replacement of labor. Importantly, it will work nicely only for autologous (personalized) cell therapies, where cost of manufacturing is very high and starting material is very variable. In this case, cost of auto- cell product will be equal cost of manufacturing, no profit. Hospitals and patients will love it and jump on it! Allogeneic cell products manufacturing will be taken (almost entirely) by industry into centralized plants.

I think, it may work especially nicely for few processes and few indications (for example, CAR T-cells in B-ALL). If your hospital wants to have multiple cell therapies for multiple indications, Prodigy may not be universal answer. Ideally, big multidisciplinary hospital would have cell therapy facility with both types devices “all-in-one” and “plug-and-play” (multiple devices for multiple processes). But if you’re looking only for getting your CAR T-cell program going in hem/oncology on a budget, Prodigy alone could be the solution.

Finally, I’d like to notice that Prodigy is just at the beginning of its way in clinical cell therapy. We may see more and better “all-in-one” devices in the future. We don’t know for sure if fundamental shift from centralized to hospital-based model will finally happen for some autologous cell products in some indications. Miltenyi’s people firmly believe (based on what I’ve learned from few talks on different conferences) that it may take years, but finally decentralized “point-of-care” model will prevail for autologous cell therapies.

What do you think? Will Prodigy change everything?

Disclaimer: This post is neither advertisement nor endorsement, but invitation for discussion. I’m not a user of CliniMACS Prodigy. I do not have any conflicts, related to Miltenyi Biotec.

{ 6 comments… read them below or add one }

Robert Chang August 8, 2016 at 10:40 am

The Prodigy strengthens the argument for decentralized manufacturing model; however, as FDA is keen to provide safe, quality material for patients, any manufacturing facility would need a quality system in place. Though having such infrastructure is feasible, it requires significant labor and capital investment for implementation and/or maintenance. For institutions that lack such infrastructure, using the Prodigy for cell therapy would be daunting.

Additionally, if clinical application is the goal, it will be interesting to see how the FDA regulates cell therapy production for the Prodigy. Miltenyi received CE designation for several antibody-magnetic bead reagents used in their CliniMACS Plus instrument; however, the FDA has only approved the CD34 Reagent System which includes all the components of separating CD34+ cells (anti-CD34 antibody, disposables, buffer, instrument). If FDA pursues similar regulatory path of considering the end product (manipulated cells) to be a “drug,” getting widespread use of the Prodigy in a decentralized model maybe limited to IND use in the US, and make reimbursement complicated.

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Carl August 8, 2016 at 3:02 pm

The reason everyone is choosing centralized manufacture is because there are too many variables in cell manufacture to make a decentralized model work. Prodigy is a classic example of a product looking for a use. Most researchers and manufacturers want versatility in their devices and manufacturers don’t like to pay for devices that can do separation but are tied up doing culture. Mostly what people are looking for are flexible closed systems like those from Terumo BCT and GE that allow individual components to be interchanged. Prodigy just appears successful because they place devices for free in hopes people will use them.

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Tim Waters August 11, 2016 at 5:36 pm

Carl –
I believe you may have some bad information. Of the large number of devices operating in the US (won’t say exactly how many but it is greater than 50 and less than 2,000), only one or two are “placed” free of charge under collaborations. We are selling the Prodigy, and it has a large number of valuable applications already in use.

Regards,
Tim Waters

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Robert Speziale August 8, 2016 at 4:13 pm

Thanks Alexey. You have begun an important discussion. But, there is more to the decision about centralized vs decentralized than just the automation. Other factors include complexity or the process, special handling as well as space requirements for the entire process. Further, these are not instruments, so I am not sure what validation has to do with it. Rather, these are GMP processe systems that will necessitate validation in place by the sponsor. That will be the challenge as a resources and technical assistance overhead cost/challenge. Otherwise, we sustain the current “cottage industry” feel of processing at local medical centers.

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Reinout Hesselink August 16, 2016 at 7:55 am

Hi Alexey,
The Prodigy is an interesting device in the sense that it is a first that tries to integrate the main steps of cell manufacturing in a single device. I do however doubt that it will ‘change everything’, as in my opinion, it has too many limitations for that. Considering that any product made in it will be a more than minimally manipulated product it will, both in FDA as well as EMA jurisdiction it will have to be prepared according to GMP. The device does not really allow for that as a standalone since for instance in process control samples are hard to take. Also, in a GMP quality system, starting material and final product will have to be tested and released as will raw materials. This will require more quality oversight than most hospitals will be able to provide. For a company, the decentralised model would pose a risk as you will have to show comparability of product for each site in which you set up the process, with all the quality oversight related to that. This would cause huge overhead.
From an operations side, using the machine to incubate the cells (about 7-10 days of expansion in a CAR-T process) would block the use of a >$100.000 device with something that can be very wall done in a $5000 incubator as well. Also, processing times for washing a full apheresis are much longer than using e.g. a Sepax and that prolonged holding time is not very well for the cells.
All in all, I do like the idea of the Prodigy but feel that it does require re-engineering in order to get to its full potential, which will not be as a point of care device.

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Chris Fisher August 25, 2016 at 3:30 am

Prodigy is being used in Europe as a device that is very open to adaption and because of this can process different cells for differing applications. It is a closed system that can operate in D Grade units (ISO 8) providing the system remains closed. To us here in the BRC GMP Unit at Guy’s Hospital, London, UK, it is a very useful machine in our repertoire of cell processors used to make Advanced Therapeutic Medicinal Products (ATMPs). We are adapting it to manufacture differing therapies to great success.
There are challenges in closing out all manufacturing processes to operate in Grade D or to extreme case Unclassified (Point of care) conditions for example: bubble point testing filters to ensure that the culture system remains closed post manufacture, weld and sealable lines so that connections and disconnections can be made sterilely.
The point of care option is difficult to understand within the European market as you require ATMPs to be certified by an EU QP to be released to market. The product must be made to its authorisation. This means that the product has to be manufactured in a certified Good Manufacturing Practice laboratory to set of authorised specifications, manufactured to validated procedures and conditions each and every time and that the product remains free from adulteration and contamination. These are parallel to the FDA requirements for phase III trials and above. To do this in a Point of Care environment exposes the process to ‘the public’. This is then considered a high risk option as the manufacturing needs to be’ safely undertaken, efficacious and fit for its indented use something you can not testify to outside the GMP environment. Therefore for a licensed medicinal product this is not an option.

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