October 20, 2020

The Niche

Knoepfler lab stem cell blog

My ongoing Q&A with Celltex on their stem cell drug production methods

How does Texas stem cell clinic Celltex make their stem cell drug? 

This is a very key question as the answers will help the stem cell field evaluate this drug’s potential safety and efficacy.

I’m calling it a “drug” because the FDA called Celltex a “drug manufacturer” and by all past FDA precedent as well as the recent federal court case that went against Regenerative Sciences, Inc., the stem cell product that Celltex produces is in fact unambiguously a drug based on current regulations. In the future, that could change and it is worth noting that Celltex appears to dispute the definition of their product as a drug.

I’ve been trying to learn more about how Celltex multiplies their stem cells by asking Celltex questions via their contact form and talking to leading experts in the cell therapy field.

Celltex has been very responsive to my questions, which I appreciate.

For example, I asked Celltex via their website:

“What growth factors are used to multiply the stem cells?”

Only one day later, Celltex responded to me by email:

 Dear Dr. Knoepfler,  

Thank you for your recent online inquiry.  The answer to your question: What growth factors are used to multiply the stem cells? can be found in our process publication (PDF).  It is attached to this email.  You will find all the details of what factors and what processes we use in our culture system.  We use the identical process as documented in the publication.    If you have any additional questions, please feel free to contact us. 

Warmest Regards,  The Celltex Team 

I’m impressed with this fast responsiveness of Celltex. Kudos!

I’ve now carefully analyzed this paper, which raised some more questions in my mind.

Most importantly, a number of the reagents described in the paper appear to be in vitro in nature.  I thought that such reagents are not usually used to grow stem cells intended for clinical use.

Is that OK? I wasn’t sure.

To dig further I have talked with experts in the field and also I sent Celltex a second question via their website:

Do you have explicit FDA permission to use DMEM and other media as well as FBS (that are all normally restricted to ONLY in vitro non-human use) to grow your stem cells for transplant into human patients?

Thanks

Paul

Yesterday I got a response back only 2 days later. Again, an impressive turn around time.

Here is what Celltex said:

Dear Dr. Knoepfler,  

Thank you for your interest in Celltex.  However, your question, “Do you have explicit FDA permission to use DMEM and other media as well as FBS (that are all normally restricted to ONLY in vitro non-human use) to grow your stem cells for transplant into human patients?”, is based on incorrect information.  FDA does not restrict DMEM and FBS to in vitro non-human use.  Both DMEM and FBS are lawful for human stem cell culture for therapeutic use.  You can find this information on FDA’s website but we have provided links for your convenience.  FDA’s 2001 approval of DMEM for ex vivo human tissue and cell culture use can be viewed here: (http://www.accessdata.fda.gov/cdrh_docs/pdf/K001447.pdf  The applicable regulation is 21 CFR 876.5585, tissue culture media for human ex vivo tissue and cell culture processing applications.  Similarly, FDA allows the use of FBS as a reagent in the manufacture of a therapeutic product.  You can see that in this 2008 FDA Guidance for its reviewers examining human gene therapy products:  http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceR  egulatoryInformation/Guidances/CellularandGeneTherapy/ucm078694.pdf    On pages 9-11 it instructs FDA reviewers on the information that must be documented when a product’s manufacture includes FBS or other animal derived reagents (that are not be present in the final product).  We hope this clarifies your understanding of the applicable regulations.    Sincerely,  

The Celltex Team  

It turns out that on one level, Celltex is correct and my question was perhaps too absolute with its “ONLY” in all caps. In talking with stem cell production experts, it turns out that in some limited cases cell products can indeed be grown in DMEM media and with FBS.

However, where a number of these experts differ with Celltex is in the broader interpretation of the FDA guidance on the use of DMEM and FBS.

The specific links mentioned by Celltex, for example, do not give blanket approval to any clinic to use in vitro media off the shelf DMEM or FBS in any stem cell product intended for human use.

Companies such as Celltex in theory might be able to use DMEM or FBS in growing their stem cells to be used for transplants, but there is no automatic FDA approval for such methodologies.

Instead, companies must ask the FDA in advance in effect for permission to use such reagents in the context of an IND (investigational new drug) application.

To the best of my knowledge, Celltex has no IND and hence does not have the FDA’s blessing to use FBS or DMEM media that are normally intended only for in vitro use. At least they did not at the time of their audit, but perhaps they have now requested permission?

To attempt to clarify this yet further, I sent a new question to Celltex yesterday asking them if they have filed an IND with the FDA. I’ll be curious of their answer. I hope they have filed an IND.

The FDA audit report of Celltex (which I discuss here) also noted the use of in vitro reagents. See observation #9 of the report below and note the “FOR RESEARCH USE ONLY” statements and the “CAUTION: Not intended for human or animal diagnostic or therapeutic uses”.

FDA Celltex

Hopefully, the FDA and Celltex over the last several months since the FDA audit have been engaging in a constructive dialogue aimed at addressing many important issues. Such issues come up for any company wanting to produce a biologic product, particularly a drug product, for human use.

FYI, Leigh Turner has written a great article about the Celltex website that I consider a must read. Check it out!