The Four Criteria and the Exceptions That Decide How an HCT/P Is Regulated

You are sitting in a consultation room and someone says the sentence that makes the whole thing sound settled: these are your own cells, so this is outside FDA.

Being autologous, meaning the cells come from you and go back into you, is not a general exemption by itself. It does appear twice in the rules, and the two places are not the same thing. One is a condition inside a four part test. The other is a separate exception for a specific situation, and it is assessed on its own terms.

This page shows you both, using the wording of the FDA guidance itself, so you can ask one precise question instead of accepting a general answer.

First, the term. The rules in this area apply to HCT/Ps, which stands for human cells, tissues, and cellular and tissue based products. That is the category the four criteria belong to. Not every product a clinic offers is an HCT/P, and this page is about the ones that are.

The four criteria, in plain English

The FDA guidance sets out the test directly. Verbatim:

“An HCT/P is regulated solely under section 361 of the PHS Act and 21 CFR Part 1271 if it meets all of the following criteria (21 CFR 1271.10(a)): 1) The HCT/P is minimally manipulated; 2) The HCT/P is intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent; 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; and 4) Either: i) The HCT/P does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function; or ii) The HCT/P has a systemic effect or is dependent upon the metabolic activity of living cells for its primary function, and: a) Is for autologous use; b) Is for allogeneic use in a first-degree or second-degree blood relative; or c) Is for reproductive use.”

Source: FDA, “Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use,” July 2020. Accessed 18 September 2026.

Read criterion four again. This is where “your own cells” actually sits. Autologous use is one of three ways to satisfy the second half of the fourth criterion, and only when the product has a systemic effect or depends on the metabolic activity of living cells. It is one branch of one criterion. It is not the test.

All four must be met. Meeting three does not put a product in this category.

What “minimally manipulated” actually means

There are two definitions, and which one applies depends on what the material is.

“minimal manipulation means: 1) For structural tissue, processing that does not alter the original relevant characteristics of the tissue relating to the tissue’s utility for reconstruction, repair, or replacement; 2) For cells or nonstructural tissues, processing that does not alter the relevant biological characteristics of cells or tissues.”

Same source.

So the question is not whether something was done to the material. Processing is expected. The question is whether the processing changed the characteristics that matter.

Which characteristics count

The guidance gives examples for the cells and nonstructural tissue definition.

“Examples of relevant biological characteristics of cells or nonstructural tissues include differentiation and activation state, proliferation potential, and metabolic activity. Processing that alters any relevant biological characteristics of cells or nonstructural tissues generally would be considered more than minimal manipulation.”

Same source.

Three named characteristics: differentiation and activation state, proliferation potential, metabolic activity.

What “homologous use” means

“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 (21 CFR 1271.3(c)), including when such cells or tissues are for autologous use.”

Same source.

The closing clause matters. Homologous use is assessed even when the donor and the recipient are the same person. Using your own tissue does not make the use homologous. The question is whether the material is doing the same basic job in the new location that it was doing in the old one.

What the guidance does not say

You will read, in summaries of this area, that culturing or expanding cells automatically exceeds minimal manipulation.

Compare that with the wording quoted above. The guidance frames it as an assessment, not a rule: processing that alters any relevant biological characteristics generally would be considered more than minimal manipulation, and proliferation potential is one of the characteristics named.

The difference is not academic. One version is a categorical rule you could apply yourself. The other is an assessment of what a specific process did to specific material. If you carry the first version into a conversation, you will ask a question the other person can correctly answer no to, and you will learn nothing.

Exceptions under 21 CFR 1271.15

A product that does not meet the four criteria is not automatically in one category. The regulations contain exceptions, and one of them is directly relevant to autologous procedures.

Read the grammar of the exception before its content, because it changes what you ask. The regulation is addressed to establishments, not to products. It says you are not required to comply… if you are an establishment that… So what qualifies, or fails to qualify, is the party doing the work under the circumstances of the procedure. A product is not a thing that “falls under” this exception on its own; a specific procedure performed by a specific establishment either fits the described circumstances or does not.

That is why the practical question is about the procedure and the party rather than about the material alone.

“Section 1271.15(b) provides: ‘You are not required to comply with the requirements of this Part if you are an establishment that removes HCT/Ps from an individual and implants such HCT/Ps into the same individual during the same surgical procedure.'”

Source: FDA, “Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception,” Guidance for Industry. Accessed 18 September 2026.

This is a different question from minimal manipulation, and the analysis is its own. A preparation can fail the four criteria while the procedure it is used in still falls within the circumstances this exception describes.

The guidance addresses the case where something is done to the material in between removal and implantation.

“Generally, an establishment that processes an autologous HCT/P prior to implantation would be required to comply with the requirements of Part 1271 and would not qualify for the exception. As a general matter, the establishment may qualify for the exception if the only processing steps taken are rinsing, cleansing, sizing, or shaping the tissue.”

And then, naming the steps directly:

“Other processing steps, including by centrifugation or filtration, for cell isolation, cell expansion, cell activation, or enzymatic digestion generally would not allow the HCT/P to remain ‘such HCT/P’ and the establishment would not qualify for the exception.”

Same source.

Rinsing, cleansing, sizing, shaping: the exception may still apply. Cell isolation, cell expansion, cell activation, enzymatic digestion: generally it would not.

What happens when the criteria are not met

Three elements of the following sentence change its meaning if they are dropped.

“If an HCT/P does not meet the criteria set out in 21 CFR 1271.10(a), and the establishment that manufactures the HCT/P does not qualify for any of the exceptions in 21 CFR 1271.15, the HCT/P will be regulated as a drug, device, and/or biological product under the FD&C Act, and/or section 351 of the PHS Act (42 U.S.C. 262), and applicable regulations, including 21 CFR Part 1271, and premarket review will be required.”

Source: FDA, Minimal Manipulation and Homologous Use guidance, July 2020. Accessed 18 September 2026.

Each of the three elements below is part of the quoted sentence, and each one narrows it.

The exception clause. The outcome applies when the criteria are not met and no 1271.15 exception applies. Both halves.

Device. The categories are drug, device, and/or biological product. Not only drug and biologic.

Premarket review will be required. This is a pathway statement, not a verdict. It does not say the product cannot exist or that offering it is unlawful in every case. It says a review step is required before marketing. Products that have been through it exist: MACI, for full-thickness cartilage defects of the knee in adults, and RYONCIL, for steroid-refractory acute graft versus host disease in children from two months old. The route is open, and what comes out of it is narrow.

A note on what this document is

The guidance carries a standard line on its pages: Contains Nonbinding Recommendations. It describes the agency’s current thinking. It is the clearest public statement of how the criteria are read, and it is not a statute.

The question this gives you

You can now replace a general question with a specific one. The broad question, is this FDA approved?, is answerable in principle but it stops one step short: it returns a yes or a no without telling you which framework produced it, and a no from the wrong branch is not an answer at all. Instead of stopping there, you can ask:

Does this product meet the four criteria in 21 CFR 1271.10(a)? If not, do this procedure and this establishment fall within an exception in 1271.15? If neither, which premarket pathway did the product go through?

Note that the middle branch changes subject on purpose. The first and third are about the product; the second is about the procedure and the party performing it, because that is who the exception is written for. Asking the middle question about the product invites an answer that sounds right and settles nothing.

Three branches, and every one of them has a checkable answer.

---

Where to go from here

If you have not yet established what the product is and whether an approved version exists, start with A Plain-English Glossary of Regenerative Medicine Terms and What Is and Is Not FDA Approved in Regenerative Medicine. If you have both and want to know what the evidence behind it looks like, go to Reading the Study a Clinic Shows You.

Before you leave this page: write the three branch question down and ask for the answer in writing. A spoken answer to a regulatory question is difficult to compare later against a document.

---

What this does not mean

This page does not tell you whether any treatment is safe, effective, or right for you. It does not say that a product outside the four criteria is unlawful, and it does not say that a product inside them is beneficial. It describes a classification framework and quotes the source so you can check it yourself. Regulatory status is one input into a decision that also involves your clinician and your own circumstances.

---

Two documents, and this page is mostly their words. Everything in quotation marks above comes from one of the two below, and the criteria themselves are quoted rather than paraphrased for a reason: a paraphrase of a four-part test is a fifth version of it. Open them and read the tests yourself.

• FDA · Minimal Manipulation and Homologous Use (guidance, July 2020) · accessed 18 September 2026
• FDA · Same Surgical Procedure Exception under 21 CFR 1271.15(b) (PDF) · accessed 18 September 2026

Written and fact-checked against the sources above on 18 September 2026. No independent expert review has taken place yet, and this page says so rather than implying one. This page is reviewed every six months and whenever the cited guidance documents change.