In the previous post, I began a review of a marketing blurb sent to my boss, Dr. David Karli, extolling the virtues of an amniotic fluid-containing product. I am sure you are wondering why I haven’t mentioned the name of the manufacturer and the offending product, but see the explanation provided in the previous post. So far, I have pointed out that the marketing blurb touted the activity of MSCs were obtained from the donor amniotic tissue, which makes the product a HCT/P, and that means that the material is not compliant with 21 CFR 1271.
In case you haven’t kept up, amniotic fluid contains water, ions, biochemicals, fetal fecal matter (aka meconium) and the occasional piece of hair. To that naturally occurring set of components, the makers of the amniotic-derived product add in a fluid taken from the culturing of MSCs obtained from the donor amniotic tissue/fluid. This is the first product I can recall that contains tissue culture fluid as an ingredient. What is fascinating to me about the presence of tissue culture fluid taken from the culturing of MSCs is that the manufacturer might run afoul of adulterating the HCT/P, as outlined in 1271.10(a)(3) [edited for format]:
(3) The manufacture of the HCT/P does not involve the combination of the cells or tissues with another article, except for water, crystalloids, or a sterilizing, preserving, or storage agent, provided that the addition of water, crystalloids, or the sterilizing, preserving, or storage agent does not raise new clinical safety concerns with respect to the HCT/P;
Consider what is in the tissue culture fluid collected by the manufacturer from the flasks containing the growing MSCs: biochemicals, including growth factors, proteins and extracellular vesicles (aka exosomes) that individually are associated with powerful physiological outcomes—causing adult cells to proliferate, supporting angiogenesis, providing anti-microbial activity, etc. For a good review of the various paracrine effects associated with MSCs see the article by Murphy, Moncivais, and Caplan. Apparently, these tissue culture-derived tbiological components are mixed with the original amniotic fluid to create the amniotic-derived product. I also infer from the blurb that MSCs are included, but can’t figure out if they are from the tissue culture flasks or are found naturally in the fluid (or tissue).
If MSCs present in the product are cultured, the product definitely is not `361-compliant, since the FDA considers cultured cell-containing materials as biologic drugs. Let’s assume that the MSCs present in the product are not cultured. I still believe the amniotic-derived product is not `361-compliant due to the presence of donor-derived viable cells, which is a violation of 1271.10(4)(i and ii), as explained in the last post. Okay, so either way the cells in the product render it non-compliant, but is there a regulatory issue with the manufacturer using the cell-free culture fluid itself?
In fact, I believe there are two ways for the product containing tissue culture-derived fluid to be found non-compliant. The first issue, as indicated in subsection 3 above, is that the FDA allows you to add water, crystalloids, or agents that sterilize, preserve, or aid in storage of the HCT/P. But according to the marketing blurb I read, the reason you want to add tissue culture fluid is that you are adding growth factors and other goodies released when the amniotic-derived MSCs are growing in culture. The problem is, I don’t see how growth factors sterilize, preserve or aid in storage of the HCT/P. So, as far as I am concerned, adding the culture fluid-containing growth factors would violate the adulteration element of 1271.10, something I never thought I would see.
However, there potentially is an even more fundamental issue with the addition of tissue culture-derived growth factors to the product—they very well could be considered by the FDA to be drugs in and of themselves.
Why is that? Let’s start with the words associated with the term “HCT/P”, which stands for “human cells, tissues and cellular and tissue-based products”. In other words, while we mostly think about 1271 as it applies to single cell preparations (e.g., SVF) or tissues like adipose, 1271 also has jurisdiction over materials that are derived from cells and tissues, which includes tissue culture fluid in my opinion, and the components therein. The marketing blurb states that the tissue culture fluid is obtained from MSCs growing in culture and that the MSCs originated with the amniotic tissue obtained from a donor. Since the original amniotic tissue is classified as an HCT/P, and the cells isolated from the HCT/P produce growth factors in culture, which subsequently are collected by the manufacturer, it sure seems like the growth factors are themselves a fluid-based HCT/P. Consequently, it is possible that the FDA could declare the growth factors found in the tissue culture fluid to be biologic drugs. And if they are considered to be drugs that would make the amniotic-derived product well and truly a biologic drug.
So, there you are, another amniotic fluid product whose manufacturer lives in a regulatory fantasy land where all HCT/Ps are FDA-compliant, but which by my count is non-compliant for three reasons. I admit that my favorite though is the possible non-compliance with 1271.10(a)(3), just because it is so rare.