Guidance for Industry 

and FDA Staff: 

Minimal Manipulation of 

Structural Tissue 

Jurisdictional Update 

For questions regarding this document, contact: 

Suzanne O’Shea, Office of Combination Products at 301-427-1934 or 

Office of Cellular, Tissue and Gene Therapies, Tissue Reference Group at 301-827-6176. 

U.S. Department of Health and Human Services 

 Food and Drug Administration 

Office of the Commissioner 

Office of Combination Products 

and 

Center for Biologics Evaluation and Research

September 2006
Guidance for Industry 

and FDA Staff: 

Minimal Manipulation of 

Structural Tissue 

Jurisdictional Update 

Additional copies are available from: 

Office of Combination Products 

Office of the Commissioner 

Food and Drug Administration 

15800 Crabbs Branch Way, Suite 200 (HFG-3), Rockville, MD 20855 

(Tel) 301-427-1934, (Fax) 301-427-1935 

Internet: http://www.fda.gov/oc/combination 

Email: combination@fda.gov 

or 

Office of Communication, Training and 

Manufacturers Assistance, HFM-40 

Center for Biologics Evaluation and Research 

Food and Drug Administration 

1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448 

(Tel) 800-835-4709 or 301-827-1800 

Internet: http://www.fda.gov/cber/guidelines.htm 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Office of the Commissioner 

Office of Combination Products 

and 

Center for Biologics Evaluation and Research 

September 2006 
 

Guidance for Industry 

and FDA Staff: 

Minimal Manipulation of 

Structural Tissue 

Jurisdictional Update 

Public Comment 

Written comments and suggestions may be submitted at any time for Agency 

consideration to the Division of Dockets Management, Food and Drug Administration, 

5630 Fishers Lane, Room 1061, (HFA-305), Rockville, MD 20852. Submit electronic 

comments to http://www.fda.gov/dockets/ecomments. When submitting comments, 

please refer to the exact title of this guidance document. Comments may not be acted 

upon by the Agency until the document is next revised or updated. 
Contains Nonbinding Recommendations 

i 

TABLE OF CONTENTS 

I. PURPOSE.............................................................................................................. 1 

II. JURISDICTIONAL INFORMATION............................................................... 2 

III. FOR FURTHER INFORMATION..................................................................... 3 
Contains Nonbinding Recommendations 

1 

Guidance for Industry and FDA Staff: 

Minimal Manipulation of Structural Tissue 

Jurisdictional Update 

This guidance represents the Food and Drug Administration's (FDA's) current thinking on 

this topic. It does not create or confer any rights for or on any person and does not 

operate to bind FDA or the public. You can use an alternative approach if the approach 

satisfies the requirements of the applicable statutes and regulations. If you want to 

discuss an alternative approach, contact the FDA staff responsible for implementing this 

guidance. If you cannot identify the appropriate FDA staff, call the appropriate number 

listed on the title page of this guidance. 

I. PURPOSE

This guidance is intended to improve the transparency of FDA’s jurisdictional 

determinations by providing additional information about the classification and 

assignment of a certain class of products. The jurisdictional information contained in this 

guidance document may be based on a past decision made in response to a Request for 

Designation (RFD) submitted pursuant to 21 CFR Part 3, or in response to a request for 

an informal jurisdictional determination. FDA’s Office of Combination Products (OCP) 

issues jurisdictional updates on selected classes of products on an ongoing basis. OCP 

selects product classes to be the subject of jurisdictional updates based on its perception 

of the current level of interest in the jurisdictional issue, the extent to which the class of 

products can be clearly described, the extent to which the existence and description of the 

class of products has been made public, and related factors. 

This guidance document provides information about the classification of products as 

human cells, tissues and cellular and tissue-based product (HCT/P’s) regulated solely 

under section 361 of the Public Health Service Act (PHS Act). Specifically, this 

guidance document discusses FDA’s current thinking on the meaning of the phrase 

“minimally manipulated” contained in 21 CFR 1271.10(a)(1), and defined (“minimal 

manipulation”) at 21 CFR 1271.3(f), as it applies to structural tissue. OCP and the 

Center for Biologics Evaluation and Research are jointly issuing this guidance. 

FDA’s guidance documents, including this guidance, do not establish legally enforceable 

responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and 

should be viewed only as recommendations, unless specific regulatory or statutory 

requirements are cited. The use of the word should in Agency guidances means that 

something is suggested or recommended, but not required. 
Contains Nonbinding Recommendations 

2 

 

II. JURISDICTIONAL INFORMATION 

FDA’s regulations set forth the criteria that must be met for an HCT/P to be regulated 

solely under section 361 of the PHS Act. These criteria are that the HCT/P must: 

• be minimally manipulated; 

• be intended for homologous use only, as reflected in the labeling, advertising, or 

other indications of the manufacturer’s objective intent; 

• not be combined with a drug or device, except for water, crystalloids, or a 

sterilizing, preserving, or storage agent, provided that the addition of the water, 

crystalloids, or sterilizing, preserving, or storage agent does not raise new clinical 

safety concerns with respect to the HCT/P; and 

• not have a systemic effect and not be dependent on the metabolic activity of living 

cells for its primary function except if for autologous use, allogeneic use in a firstdegree or second-degree blood relative, or reproductive use.1

FDA regulations further define “minimal manipulation” for structural tissue as 

“processing that does not alter the original relevant characteristics of the tissue relating to 

the tissue’s utility for reconstruction, repair, or replacement.”2

 

FDA has received several RFD’s requesting a determination of whether or not certain 

HCT/P’s will be regulated solely under section 361 of the PHS Act based on the 

manipulation the product undergoes during processing.3 For purposes of determining 

whether a structural tissue product is minimally manipulated, a tissue characteristic is 

“original” if it is present in the tissue in the donor. A tissue characteristic is “relevant” if 

it could have a meaningful bearing on how the tissue performs when utilized for 

reconstruction, repair, or replacement. A characteristic of structural tissue would be 

relevant when it could potentially increase or decrease the utility of the original tissue for 

reconstruction, repair or replacement. 

Accordingly, FDA’s determination of whether structural tissue is eligible for regulation 

solely under section 361 of the PHS Act has encompassed a consideration of all the 

potential effects, both positive and negative, of the alteration of a particular characteristic 

on the utility of the tissue for reconstruction, repair or replacement, i.e., changing the 

1

 21 CFR 1271.10(a). 

2

 21 CFR 1271.3(f)(1). For cells or nonstructural tissue, minimal manipulation is processing that does not 

alter the relevant biological characteristics of cells or tissues. 21 CFR 1271.3(f)(2). 3

 FDA has formed a committee known as the Tissue Reference Group (TRG) consisting of representatives 

from the Center for Biologics Evaluation and Research, the Center for Devices and Radiological Health, 

the Office of Chief Counsel, and the Office of Combination Products to make initial recommendations on 

several issues pertaining to HCT/P’s, including whether the product may be regulated solely under section 

361 of the PHS Act. TRG recommendations may be appealed through the Request for Designation 

process, as outlined in 21 CFR Part 3. Further information about the TRG may be found at 

http://www.fda.gov/cber/tissue/tisrefgrp.htm. 
Contains Nonbinding Recommendations 

3 

characteristic could improve or diminish the tissue’s utility. Once FDA has determined, 

based on the data and information before it, that processing has altered an original 

characteristic of a structural tissue, and that the characteristic is relevant in that it has a 

potential effect on the utility of the tissue for reconstruction, repair, or replacement, the 

agency has considered the tissue to be more than minimally manipulated and not eligible 

for regulation solely under section 361 of the PHS Act.4 In such a case the structural 

tissue will be regulated as a drug, device and/or biological product under the Federal 

Food, Drug, and Cosmetic Act and/or section 351 of the PHS Act.5

III. FOR FURTHER INFORMATION 

For an initial determination whether a particular HCT/P will be regulated solely under 

section 361 or regulated as a drug, device or biological product, contact: 

Office of Cellular, Tissue and Gene Therapies 

Tissue Reference Group6

Telephone: 301-827-6176 

The Office of Combination Products may also be contacted at 

Suite 200, HFG-3 

15800 Crabbs Branch Way 

Rockville, Maryland 20855 

Telephone: 301-427-1934 

e-mail: combination@fda.gov

A formal determination of the classification or assignment of a particular product may be 

made through the Request for Designation (RFD) process. Further information about the 

RFD process is available at 21 CFR Part 3, www.fda.gov/oc/ombudsman/part3&5.htm

and in the document “Guidance for Industry and FDA: How to Write a Request for 

Designation (RFD),” available at www.fda.gov/oc/combination/. We recommend that 

sponsors call OCP at 301-427-1934 to discuss their particular situation before submitting 

an RFD. 

OCP is always available as a resource to you. We encourage you to contact OCP if you 

have any questions about the jurisdiction of your product. 

 

4

 21 CFR 1271.10 

5

 21 CFR 1271.20 

6

 Further information about FDA’s regulation of HCT/P’s and the Tissue Reference Group may be found 

at http://www.fda.gov/cber/tiss.htm.