Section 2 of 10 — FDA regulatory pathways

The 351(a) BLA Pathway vs. the 361 HCT/P Pathway

The single most important — and most frequently misstated — regulatory question in this field: is a given cell or exosome product regulated as a full biologic drug, or as a lightly-regulated tissue product? The answer turns on a specific four-part federal test, not on marketing language.

Educational information only — not medical or legal advice. This page is for general public education about FDA regulation of regenerative medicine. It does not diagnose, treat, or recommend treatment for any condition, and it is not a substitute for consulting a licensed physician about a medical question or a licensed attorney about a legal question. See the full disclaimer.

On this page:

Statutory basis
The four-criteria test
351(a) vs. 361 at a glance
Where exosome products typically land
FDA guidance documents

1. Statutory basis

Two different sections of the Public Health Service Act (PHS Act) govern human cell and tissue products:

Section 351 of the PHS Act, codified at 42 U.S.C. § 262, requires a Biologics License Application (BLA) — full FDA premarket review of safety, purity, and potency — before a biological product can be introduced into interstate commerce. Before a 351(a) product can even be tested in humans, the sponsor must have an effective Investigational New Drug (IND) application on file with FDA.
Section 361 of the PHS Act, codified at 42 U.S.C. § 264, is a narrower communicable-disease-control authority. FDA has used it to create a lighter-touch framework — registration and listing only, no premarket approval — for a defined category of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps), set out in 21 CFR Part 1271.

Which pathway applies to a given product is not a matter of what the seller calls it. It is a factual and legal determination governed by a specific four-part regulatory test.

2. The four-criteria test — 21 CFR § 1271.10(a)

An HCT/P is regulated solely under Section 361 (the lighter pathway) only if it meets all four of the following criteria. Failing even one moves the product into full drug/biologic regulation under Section 351(a):

Minimal manipulation. For cells or non-structural tissue, the processing must not alter the relevant biological characteristics of the cells or tissue (21 CFR § 1271.3(f)). FDA's 2020 guidance states that where information does not establish minimal manipulation, FDA treats the processing as "more than minimal manipulation," disqualifying the product from Section 361.
Homologous use only. The product must perform "the same basic function or functions in the recipient as in the donor" (21 CFR § 1271.3(c)), as reflected in labeling, advertising, or the manufacturer's objective intent.
No combination with another article, except water, crystalloids, or a sterilizing/preserving/storage agent that does not raise new clinical safety concerns.
No systemic effect and not dependent on the metabolic activity of living cells for its primary function — unless the product is for autologous use (the patient's own cells), allogeneic use in a first- or second-degree blood relative, or reproductive use.

If a product fails any one of these four criteria, it is a drug and/or biologic requiring an IND for human testing and a BLA for marketing — the full Section 351(a) pathway.

3. 351(a) vs. 361 at a glance

	Section 351(a) biologic	Section 361 HCT/P
Statutory basis	42 U.S.C. § 262	42 U.S.C. § 264; 21 CFR Part 1271
Premarket review	Full FDA review of safety, purity, potency (BLA)	None — registration and listing only
Human testing	Requires an effective IND	No IND required if all four criteria are met
Manufacturing standard	Full cGMP (21 CFR Parts 210/211) plus biologics-specific rules (21 CFR Parts 600–680)	Current Good Tissue Practice, cGTP (21 CFR Part 1271, Subpart D)
Typical use	Systemic / therapeutic-claim products; cultured or expanded cell products; most exosome products	Minimally manipulated, homologous-use tissue (e.g., certain bone or skin grafts used for structural repair)

4. Where exosome products typically land

FDA has stated directly, in a December 2019 public safety notification: "There are currently no FDA-approved exosome products... As a general matter, exosomes used to treat diseases and conditions in humans are regulated as drugs and biological products under the Public Health Service Act and the Federal Food Drug and Cosmetic Act and are subject to premarket review and approval requirements." That notification followed multiple serious adverse events in patients treated with unapproved exosome products, reported through the CDC and Nebraska DHHS.

As a matter of the regulatory text itself: cell culture, cell expansion, and isolation of exosomes from conditioned media are generally treated by FDA as "more than minimal manipulation." And using an exosome product for systemic anti-inflammatory signaling, wound healing, or tissue repair — rather than the structural/cushioning function Wharton's Jelly serves in the umbilical cord itself — is generally non-homologous use. On the facts most commercial exosome products present, both Criterion 1 and Criterion 2 are typically failed, which independently disqualifies the product from Section 361 and places it under Section 351(a): IND required for any human use, BLA required for marketing.

Analysis, not a direct FDA quote A separate, purely regulatory-text observation: 21 CFR § 1271.3(d)(3) excludes "secreted or extracted human products, such as milk, collagen, and cell factors" from the definition of an HCT/P in the first place (with an exception for semen). Because exosomes are secreted extracellular vesicles, there is a plausible reading of the regulatory text under which certain exosome products might not even reach the four-criteria test — they could fall outside Part 1271 entirely and default straight to drug/biologic regulation. FDA's 2020 minimal-manipulation/homologous-use guidance states this category of question is "beyond the scope" of that guidance and does not address exosomes by name. This is presented here as a legal-text observation, not as a stated FDA holding on exosome products specifically, and should be verified with counsel before being asserted as settled.

5. FDA guidance documents referenced on this page

FDA, Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use (Guidance for Industry and FDA Staff, July 2020).
FDA, Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception (Guidance for Industry, November 2017).
FDA, Framework for the Regulation of Regenerative Medicine Products (policy landing page).