The previous Greyledge post contained some of my observations on the issues cited in the FDA’s Warning Letter that was sent to Ms. Comella and her SVFing clinic, US Stem Cell Clinic (USSCC) on August 24th. The Warning Letter addressed substantial operational failures in the protocols Ms. Comella and her clinic have used to produce stromal vascular fraction (SVF) preparations for treating a wide variety of pathologies.
Related Post: See Part Two for my views on USSCC’s SVF preparations.
I will continue in this post with reviewing specific findings reported by the FDA in their Warning Letter that I believe aren’t associated with a cGMP Quality standard, which some have argued is the only reason the FDA took issue with the clinic’s operation. Dream on.
Let’s continue with the following observation:
6. Failure to have a written record of major equipment cleaning, maintenance and use [21 CFR 211.182]. Specifically, your firm lacks records reflecting that cleaning, sanitizing, and inspections of equipment have been performed prior to, during, or after the manufacture of each batch of SVF product.
A fundamental requirement when processing human tissue is that only one patient’s tissue can be exposed in an aseptic processing environment at a time (i.e., within a hood). While this requirement is a part of cGMP, it also is just plain old common sense—you don’t want to take a chance at mixing up one patient’s SVF with that of another patient. Item 6 indicates that there were no records of cleaning the processing area between different patients’ preparations. If you don’t document that the area is free of the components that were used for the previous patient, how do you know you won’t mix up something? The other actions, like documenting the maintenance of major equipment, definitely come right out of cGMP, but at some level even a non-cGMP processing facility needs to track how its equipment is functioning.
Another implication of the FDA’s citation about a lack of written records for equipment in Item 6 is that USSCC apparently wasn’t tracking operational integrity of the equipment it relies on to maintain an aseptic environment. For example, at Vet-Stem (where I established a technology platform to create SVF in the veterinary market), a patient’s fat tissue was processed in a biological safety cabinet (i.e., a Class II Type 2A BSC), which produces a sterile environment within the hood. We kept a log of the certification of each hood, performed on an annual basis, which meant that the airflow and level of sterility met the specifications Vet-Stem relied on to minimize potential contamination of the fat tissue while being processed. I don’t know if USSCC uses BSCs or not, but not to track the functionality of critical equipment is a problem waiting to happen.
As indicated in Item 8, the FDA definitely went all cGMP on USSCC when they itemized the clinic’s failure to establish appropriate conditions and standards that ensure the integrity of all of the materials coming into contact with the patient’s fat tissue; as well as the integrity of the final SVF itself:
8. Failure to maintain laboratory controls that include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure the components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality and purity [21 CFR 211.160(b)]. For example, you have not established procedures for testing the final SVF product, including tests for identity, strength, quality, and purity.
To be fair, the clinic undoubtedly used sterile components for any item coming into contact with a patient’s tissue. But in a cGMP Quality environment, not only would the clinic need to do all of the tasks listed in Item 8 with all of the critical components, but they would need to start by purchasing components only from qualified vendors. And how do you qualify vendors? You need to establish, at a minimum, a Quality Plan for each vendor, including questionnaires, phone audits, on-site audits, etc. Obviously, being compliant with cGMP definitely takes a lot of effort; an effort well beyond the scope of operating a medical clinic.
While most of the tasks highlighted in Item 8 are tied almost directly to cGMP, the FDA included the following comment:
For example, you have not established procedures for testing the final SVF product, including tests for identity, strength, quality, and purity.
Now, if you are making small molecule legal drugs you definitely need to address testing of the final drug product to ensure that it contains what it is supposed to, at the right amount, with the right combination of other ingredients and is free of microbial or other types of contamination. But USSCC makes SVF, a short-lived preparation that contains viable cells, so what testing might be reasonable? Well, they could at least have counted the number of cells and more importantly how many were still alive after processing. From the comment the Feds made, it would seem that even that limited assessment wasn’t performed. All of the SVF preparations at Vet-Stem were assessed for number and viability of the cells present, starting with the very first commercial SVF preparation I produced.
Along the same lines, the FDA cited USSCC’s failure to qualify the collagenase the clinic used to process a patient’s fat tissue in Item 10:
For example, the (b)(4) used in the manufacture of the SVF product is for research use only, as stated on the manufacturer’s product insert which was provided by your firm. Your firm lacks evidence, such as testing, to demonstrate this component meets all specifications of identity, strength, quality, and purity.
While any number of materials could be inserted into the “(b)(4)” redaction in the excerpt, most likely only collagenase would be marked “for research use only”. Also, Ms. Comella indicated in her rebuttal letter that they used collagenase during the processing of fat tissue. Why is the FDA making such a big deal about the lack of characterization of the collagenase the clinic used? Because a collagenase preparation intended for research use very well could be full of endotoxin (a bad thing) and contain a real mishmash of various enzymatic activities, only one of which results in the degradation of collagen itself. In other words, if you don’t use medical grade collagenase (which wouldn’t be marked for research use only), you really won’t know what is in a vial marked “collagenase”, unless you evaluate it. I recall from my searches for a “good” collagenase preparation at Vet-Stem that collagenase from different manufacturers could vary in their effectiveness at digesting fat tissue by a factor of 10 or more. But at least Vet-Stem had a validated protocol for qualifying its collagenase.
Why is this adverse finding particularly problematic when your processing involves research-grade collagenase? Because without a functional assessment of a new lot of collagenase you might not be digesting the fat tissue very effectively and the yield of cells will go way down. Low cell yield could reduce the potential effectiveness of the SVF preparation. And in the case of USSCC, since they apparently don’t count the number of cells they wouldn’t know how effective their collagenase was or wasn’t. As far as I am concerned, none of this has anything to do with cGMP per se. Frankly, it is just common sense to test for potency when your manufacturing process involves an enzyme.
I will finish my review of the non-cGMP linked observations cited in the Warning Letter from the FDA to Ms. Comella and her clinic in the next post.