Research
What a cell or tissue product is, and why exosomes are not one
A separate federal rulebook covers products made of human cells and tissue. Understanding which side of its line something falls on tells you whether it needed approval before it was ever sold.
A second rulebook, sitting beside the drug rules
Peptide clinics often list other things on the same menu. Exosomes, umbilical cord products, cells taken from fat. Those sit under a different part of the federal regulations, and the difference decides how much review they had.
The rulebook covers what it calls human cells, tissues, and cellular and tissue-based products. The definition is broad: "articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient."
The regulation lists examples of its own, including bone, ligament, skin, cornea, heart valve and blood-forming stem cells from cord blood.
A peptide made by chemical synthesis contains no human cells. So the part below is not about peptides. It is about what a peptide seller may be listing next to them.
Four conditions, all of which have to hold
The whole part turns on one test. Meet it, and a product is regulated only under the public health statute and this part. Fail any piece, and something much heavier applies.
The regulation is explicit that the test is conjunctive. A product qualifies "if it meets all of the following criteria," and then lists them.
It has to be minimally manipulated. It has to be "intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer's objective intent." Its manufacture must not involve combining the cells with another article, apart from water, crystalloids, or a sterilizing, preserving or storage agent that raises no new clinical safety concerns.
And the fourth criterion splits. One branch covers a product with no systemic effect that does not depend on living cells for its main function. The other covers a product that does, and is for the person it came from, a close blood relative, or reproductive use.
The two words that decide most cases
Two defined terms carry the weight, and both are narrower than the marketing around them.
Homologous use means "the repair, reconstruction, replacement, or supplementation of a recipient's cells or tissues with an HCT/P that performs the same basic function or functions in the recipient as in the donor."
Read what that excludes. Tissue that cushions a joint in the donor, sold to treat something unrelated, is not doing the same basic function. The criterion also looks at advertising, so a claim on the website is evidence of intended use.
Minimal manipulation has two definitions, depending on the material. For structural tissue it means processing that does not alter the original relevant characteristics relating to reconstruction, repair or replacement. For cells and nonstructural tissue it means processing that does not alter their relevant biological characteristics.
What happens when the test fails
This is the part that matters to a buyer, and it is written out in a single sentence.
Where a product does not meet the criteria and no exception applies, the regulation says it "will be regulated as a drug, device, and/or biological product." That is under the Act or the public health statute, along with the applicable regulations.
So failing the test does not move a product into a gap. It moves it into the ordinary approval pathway, which means it needed an approval or a license before it was marketed.
The regulation also points at the manufacturing rules, which is easy to miss. Products that fall out of the light-touch category still have to follow the donor-eligibility and good tissue practice procedures on top of everything else.
Why exosomes are not in this part at all
The definition of a cell or tissue product carries a list of things it does not cover, and one entry answers the exosome question directly.
Not covered are "Secreted or extracted human products, such as milk, collagen, and cell factors." Semen is carved back in; nothing else on that line is.
An exosome is a vesicle secreted by cells. A preparation of them is a secreted human product, so it is outside this part rather than inside it, and the four-criteria test never gets applied.
That is the opposite of a shortcut. Being outside means the product is looked at as a drug or a biological product from the start, with no lighter category available to it.
What the agency has said to consumers about these products
The agency published a consumer alert about regenerative medicine products, dated July 2020, and it is unusually blunt for a page written for the public.
On stem cells it says the only products approved for use in the United States are blood-forming stem cells derived from umbilical cord blood. Those are approved for disorders affecting blood production, and the alert adds that they are "not approved for other uses."
On exosomes it says that as a general matter, exosome products intended to treat diseases or conditions in humans require approval. The alert then states: "There are currently no FDA-approved exosome products."
That sentence describes what the agency wrote in July 2020. It is a statement from a dated page rather than a live reading of the approvals register, and it should be treated that way.
The exceptions, and the one people invoke
A handful of situations sit outside the part entirely, and one of them turns up in clinic marketing.
The part does not apply to an establishment that "removes HCT/P's from an individual and implants such HCT/P's into the same individual during the same surgical procedure."
Every element of that is load-bearing. Same individual, and the same surgical procedure. A sample taken, sent away, processed and returned on another day is not what the exception describes.
Other exceptions cover nonclinical scientific or educational use, carriers moving product in the usual course of business, and facilities that only receive or store for use inside their own walls.
What a buyer can actually check
Very little of this is visible on a product page, which is itself the useful finding. Three questions get you most of the way.
What is the material, and where did it come from? Cord blood, amniotic fluid, fat and exosome preparations are all different starting points with different answers, and a page that will not say which it is has told you something.
What is it claimed to do? A claim to treat a condition unrelated to the tissue's original function is the homologous-use criterion failing in public, and the regulation says advertising counts as evidence of intent.
And is any approval named? Where a product falls outside the light-touch category, an approval or license is what the rules require. A page that mentions neither, and instead points at a registration number, is describing a different thing.
Key takeaways
- A separate part of the federal regulations covers products made of human cells and tissue.
- Its light-touch category requires all four criteria at once, not a choice among them.
- Homologous use means the same basic function in the recipient as in the donor.
- Advertising counts as evidence of a product's intended use under the criterion.
- Secreted or extracted human products, including exosome preparations, are excluded from the part.
- Falling outside the part means being treated as a drug or biological product, which is heavier.
- A consumer alert dated July 2020 states there were no approved exosome products.
Frequently asked questions
Are exosome products covered by the cell and tissue rules?
No, and the reason is an exclusion rather than a test. The definition lists articles that are not cell or tissue products, and it names secreted or extracted human products such as milk, collagen and cell factors. An exosome preparation is a secreted product, so the part does not apply. That is not a lighter regime. It means the product is considered as a drug or a biological product, which is the pathway that requires approval before marketing.
What does "minimally manipulated" actually mean?
It has two definitions and the material decides which applies. For structural tissue it means processing that does not alter the original relevant characteristics of the tissue relating to its utility for reconstruction, repair or replacement. For cells or nonstructural tissues it means processing that does not alter their relevant biological characteristics. Both are written as an absence of change, so the more a process does to the material, the harder the criterion is to meet.
What is homologous use?
The regulation defines it as repair, reconstruction, replacement or supplementation of a recipient's cells or tissues with a product that performs the same basic function or functions in the recipient as in the donor. The criterion also says intended use is reflected by labeling, advertising or other indications of the manufacturer's objective intent. So a claim made in marketing is part of how the question is answered, not separate from it.
If a product fails the four criteria, is it unregulated?
The opposite. The regulation says that a product failing the criteria, where no exception applies, will be regulated as a drug, device or biological product under the Act or the public health statute and the applicable regulations. It also points at the donor-eligibility and good tissue practice procedures, which continue to apply. Failing the test moves a product into a heavier pathway, not out of one.
Does the same-day exception cover a clinic sending a sample to a lab?
Not as written. The exception covers an establishment that removes the material from an individual and implants it into that same individual during the same surgical procedure. Same person and same procedure are both conditions. Material collected, shipped elsewhere for processing and returned for a later appointment does not match the sentence, whatever the process is called.
Do any of these rules apply to peptides?
Not to a peptide made by chemical synthesis, because the part covers articles containing or consisting of human cells or tissues. The reason to know the rules is that these products are frequently offered on the same menu as peptides, by the same clinics, with similar language. The regulatory category is completely different, and so is the amount of review a product went through before it reached a price list.
Sources
Each document below is named as it names itself, with the date printed on that document rather than the day it was read.
- Title 21 Code of Federal Regulations section 1271.10, Are my HCT/P's regulated solely under section 361 of the PHS Act and the regulations in this part, and if so what must I do — the four conjunctive criteria at (a), including minimal manipulation, homologous use as reflected by labeling and advertising, the limit on combination with another article, and the systemic-effect branch — Electronic Code of Federal Regulations, Office of the Federal Register, November 2004
- Title 21 Code of Federal Regulations section 1271.3, How does FDA define important terms in this part — homologous use at (c), the definition of HCT/Ps and the list of articles that are not HCT/Ps at (d), including secreted or extracted human products such as milk, collagen and cell factors, and the two definitions of minimal manipulation at (f) — Electronic Code of Federal Regulations, Office of the Federal Register, January 2001
- Title 21 Code of Federal Regulations section 1271.20, stating that an HCT/P not meeting the criteria in section 1271.10 and not qualifying for an exception will be regulated as a drug, device and/or biological product — Electronic Code of Federal Regulations, Office of the Federal Register, August 2016
- Title 21 Code of Federal Regulations section 1271.15, Are there any exceptions from the requirements of this part — including the same individual, same surgical procedure exception at (b) — Electronic Code of Federal Regulations, Office of the Federal Register, January 2001
- Consumer Alert on Regenerative Medicine Products Including Stem Cells and Exosomes, carrying its own printed date line, and stating that there were no FDA-approved exosome products — U.S. Food and Drug Administration, July 2020