Regulation of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) - Small Entity Compliance Guide: Guidance for Industry

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Regulation of Human Cells, Tissues,
and Cellular and Tissue-Based
Products (HCT/Ps)
Small Entity Compliance Guide
Guidance for Industry
This guidance is for immediate implementation.
FDA is issuing this guidance for immediate implementation in accordance with 21 CFR
10.115(g)(4)(i). Submit one set of either electronic or written comments on this guidance at any
time. Submit electronic comments to https://www.regulations.gov/. Submit written comments
to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers
Lane, Rm. 1061, Rockville, MD 20852. You should identify all comments with docket number
Docket No. FDA-2022-D-0563
Additional copies of this guidance are available from the Office of Communication, Outreach
and Development (OCOD), 10903 New Hampshire Ave., Bldg. 71, Rm. 3128, Silver Spring,
MD 20993-0002, or by calling 1-800-835-4709 or 240-402-8010, or email ocod@fda.hhs.gov, or
from the Internet at https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-
regulatory-information-biologics.
For questions on the content of this guidance, contact OCOD at the phone numbers or email
address listed above.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research
November 2022

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Table of Contents
I. 	INTRODUCTION ........................................................................................................... 1
II. 	QUESTIONS AND ANSWERS ..................................................................................... 2
GENERAL ........................................................................................................... 2
REGISTRATION AND LISTING .................................................................... 4
DONOR ELIGIBILITY ..................................................................................... 9
CURRENT GOOD TISSUE PRACTICE ....................................................... 10
FDA INSPECTION AND ENFORCEMENT OF ESTABLISHMENTS
DESCRIBED IN 21 CFR 1271.10 .................................................................... 13
III. 	REFERENCES .............................................................................................................. 18

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Regulation of Human Cells, Tissues, and Cellular and Tissue-Based
Products (HCT/Ps)
Small Entity Compliance Guide
Guidance for Industry
This guidance represents the current thinking of the Food and Drug Administration (FDA or
Agency) on this topic. It does not establish any rights for any person and is not binding on FDA
or the public. You can use an alternative approach if it satisfies the requirements of the
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff
responsible for this guidance as listed on the title page.
I. 	INTRODUCTION
The Food and Drug Administration (FDA) has prepared this guidance in accordance with section
212 of the Small Business Regulatory Enforcement Fairness Act (Public Law 104-121). It is
intended to help small entity establishments that manufacture1 human cells, tissues, or cellular or
tissue-based products (HCT/Ps) better understand the comprehensive regulatory framework for
HCT/Ps, set forth in Title 21 of the Code of Federal Regulations, part 1271 (21 CFR 1271).2
Section 21 CFR 1271.3 provides definitions for important terms used in 21 CFR 1271.
This guidance document supersedes the guidance of the same title dated August 2007.
In general, FDA’s guidance documents 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.
1 “Manufacture” means, but is not limited to, any or all steps in the recovery, processing, storage, labeling,
packaging, or distribution of any human cell or tissue, and the screening or testing of the cell or tissue donor (21
CFR 1271.3(e)).
2 See “Human Cells, Tissues, and Cellular and Tissue-Based Products; Establishment Registration and Listing;”
Final Rule, 66 FR 5447 (January 19, 2001); “Eligibility Determination for Donors of Human Cells, Tissues, and
Cellular and Tissue-Based Products;” Final Rule, 69 FR 29786 (May 25, 2004); “Current Good Tissue Practice for
Human Cell, Tissue, and Cellular and Tissue-Based Product Establishments; Inspection and Enforcement;” Final
Rule, 69 FR 68612 (November 24, 2004).

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II. 	QUESTIONS AND ANSWERS
GENERAL
1. 	Where can an establishment find the criteria to determine how their
HCT/Ps will be regulated?
21 CFR 1271.10(a) sets out the criteria that form the foundation of FDA’s tiered,
risk-based approach to regulating HCT/Ps. HCT/Ps that meet all of the criteria in
21 CFR 1271.10(a) are subject only to regulation under section 361 of the Public
Health Service Act (PHS Act) and the regulations in 21 CFR part 1271. An
HCT/P that falls into this category is sometimes referred to as a “361 HCT/P” and
no premarket authorization is required.
If an HCT/P does not meet all 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 listed in 21 CFR 1271.15, the HCT/P will be regulated as a drug,
device, and/or biological product under section 351 of the PHS Act and/or the
Federal Food, Drug, and Cosmetic Act (FD&C Act), and applicable regulations,
including 21 CFR part 1271, and premarket review will generally be required.
Please note, the regulatory status of products identified as not being HCT/Ps (see
21 CFR part 1271.3(d)(1)-(8)) is beyond the scope of this guidance.
2. 	How can HCT/P manufacturers get more information about the
appropriate regulatory considerations for their HCT/P?
To further assist HCT/P manufacturers, FDA issued the Guidance for Industry,
“Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-
Based Products: Minimal Manipulation and Homologous Use”, dated November
2017 and updated July 2020 (Ref.1). This guidance is intended to improve
stakeholders’ understanding of the definitions of minimal manipulation in 21 CFR
1271.3(f) and homologous use in 21 CFR 1271.3(c). This guidance is also
intended to facilitate stakeholders’ understanding of how the regulatory criteria in
21 CFR 1271.10(a)(1) and (2) apply to their HCT/Ps.
In addition, FDA published the Guidance for Industry, “Same Surgical Procedure
Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the
Scope of the Exception”, dated November 2017 (SSPE Guidance) (Ref. 2). This
guidance is intended to provide stakeholders with the FDA’s current thinking on
the scope of the exception set forth in 21 CFR 1271.15(b). If the exception in 21
CFR 1271.15(b) applies, the establishment is not required to comply with the
requirements of 21 CFR part 1271.
FDA provides two mechanisms through which a manufacturer may obtain a
recommendation or decision regarding the classification of an HCT/P:

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1) 	The Tissue Reference Group (TRG), which includes representatives from
CBER and CDRH, provides product sponsors with an informal process
through which they may obtain an Agency recommendation regarding the
application of the criteria in 21 CFR 1271.10(a) to their HCT/Ps for a
given indication. Information about this process as well as what you may
want to include to facilitate review of your request can be found at:
https://www.fda.gov/vaccines-blood-biologics/tissue-tissue-
products/tissue-reference-group.
2) 	A Request for Designation (RFD) may be submitted to the Office of
Combination Products (OCP) to obtain a formal Agency decision
regarding the regulatory identity or classification of an HCT/P (21 CFR
part 3). A description of that process and information on how to submit an
RFD can be found at: https://www.fda.gov/combination-products/rfd-
process. Additional information may be found in FDA’s Guidance for
Industry, “How to Write a Request for Designation,” dated April 2011,
https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/how-write-request-designation-rfd. You may also submit a
Pre-RFD to OCP to obtain preliminary, feedback on the classification for
your HCT/P. A description of the Pre-RFD process as well as assistance
on how to prepare a Pre-RFD may be found in FDA’s Guidance for
Industry, “How to Prepare a Pre-Request for Designation (Pre-RFD),”
https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/how-prepare-pre-request-designation-pre-rfd.
3. 	Which subparts of 21 CFR part 1271 apply to HCT/Ps3 regulated solely
under section 361 of the PHS Act?
For HCT/Ps regulated solely under section 361 of the PHS act, the subparts of 21
CFR part 1271 apply as follows:
• 	subparts A through C apply to all 361 HCT/Ps;
• 	subpart D applies only to non-reproductive 361 HCT/Ps, with the
exception of 21 CFR 1271.150(c) and 1271.155, which apply to
all 361 HCT/Ps;
• 	subpart E applies only to non-reproductive 361 HCT/Ps; and,
• 	subpart F applies to all 361 HCT/Ps.
4. 	Which subparts of 21 CFR part 1271 apply to HCT/Ps regulated as
drugs, devices, and/or biological products?
For HCT/Ps regulated as drugs, devices, and/or biological products, the subparts
of 21 CFR part 1271 apply as follows:
3 Subparts C through F of 21 CFR part 1271 do not apply to HCT/Ps recovered before May 25, 2005.

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• 	subparts A, C, and D apply to all these HCT/Ps; and,
• 	subparts B, E, and F do not apply.
5. 	For an establishment that manufactures an HCT/P regulated as a drug,
device, and/or biological product, what must the establishment do if a
requirement in 21 CFR part 1271 conflicts with a requirement in 21 CFR
parts 210, 211, or 820?
In addition to current good tissue practice (CGTP) requirements in 21 CFR part
1271, subpart D, current good manufacturing practice (CGMP) requirements in 21
CFR parts 210 and 211 for drugs and biological products, or quality system (QS)
regulation requirements in 21 CFR part 820 for devices apply to an HCT/P
regulated as a drug, device, and/or biological product, as appropriate. In the event
that a regulation in 21 CFR part 1271 is in conflict with a requirement in 21 CFR
parts 210, 211, or 820, the establishment must follow the requirements that are
more specifically applicable to the product, rather than the more general
requirements (21 CFR 1271.150(d)).
For additional information about the CGTP requirements that would not be partly
or completely covered by a corresponding CGMP regulation or QS regulation
requiring the same practice, see the Guidance for Industry: “Current Good Tissue
Practice (CGTP) and Additional Requirements for Manufacturers of Human
Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)” dated
December 2011 (CGTP Guidance) (Ref. 3).
REGISTRATION AND LISTING
1. 	Which establishments are required to register and list their HCT/Ps?
All establishments that manufacture 361 HCT/Ps (361 HCT/P establishments)
must register and list their HCT/Ps with FDA (see 21 CFR 1271.1(b)(1),
1271.10(b), and 1271.21). Manufacturers of HCT/Ps that are regulated as drugs,
devices, and/or biological products under section 351 of the PHS Act and/or the
FD&C Act and applicable regulations, must register and list their products in
accordance with 21 CFR part 2074 or 8075, as applicable, rather than 21 CFR part
1271 (21 CFR 1271.1(b)(2)).6
4 See FDA’s Drug Registration and Listing webpage (available at https://www.fda.gov/drugs/guidance-compliance-
regulatory-information/drug-registration-and-listing-system-drls-and-edrls) for more information.
5 See FDA’s Device Registration and Listing webpage (available at https://www.fda.gov/medical-devices/how-
study-and-market-your-device/device-registration-and-listing) for more information.
6 In 2016, FDA revised 21 CFR 1271.1(b)(2) and 1271.20 to require establishments that manufacture HCT/Ps
regulated as drugs and/or biological products to register and list following the procedures in 21 CFR part 207 and
establishments that manufacture HCT/Ps regulated as devices to register and list following the procedures in 21 CFR
part 807. (see 81 FR 60169, 60223, August 31, 2016). However, the agency inadvertently omitted a conforming
amendment to 21 CFR 807.20(d) to reflect those changes. The agency intends to update its regulations to correct the
error.

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FDA does not require establishments that manufacture HCT/Ps regulated as
drugs, devices, and/or biological products that are only for use in research under
an investigational new drug application (IND) (21 CFR part 312) or an
investigational device exemption (IDE) (21 CFR part 812) to register and list
those HCT/Ps in accordance with 21 CFR part 207 or 807 if they do not engage in
other activities that would require them to register (21 CFR 207.13(e), 807.65(f)
and 812.1).
2. 	Must foreign establishments that manufacture HCT/Ps imported for
distribution in the United States register and list their HCT/Ps?
Yes. All foreign establishments manufacturing 361 HCT/Ps that are imported or
offered for import into the United States (U.S.) must register and list their 361
HCT/Ps with FDA (see 21 CFR 1271.1(b)(1), 1271.10(b), and 1271.21). It is a
requirement for such foreign establishments to submit certain information
described in 21 CFR 1271.25(a)(5)-(6), including the name, address, phone
number, and email address of the U.S. agent(s) (someone located in the United
States as a contact for inspection and other purposes) and of each importer that is
known to the establishment at the time of initial registration or when submitting
the annual registration update. If the HCT/Ps being imported or offered for import
into the U.S. are regulated as drugs, devices, and/or biological products under
section 351 of the PHS Act and/or the FD&C Act, the foreign establishment must
register and list in accordance with 21 CFR part 207 or part 807, as applicable
(see 21 CFR 1271.1(b)(2)).
3. 	Which establishments are excepted from HCT/P registration and listing?
If an establishment qualifies for any of the exceptions listed in 21 CFR 1271.15,
the establishment does not have to register and list their HCT/Ps. For HCT/Ps
regulated as drugs, devices, and/or biological products under section 351 of the
PHS Act and/or the FD&C Act, exemptions from registration and listing
requirements are set forth in section 510(g) of the FD&C Act, 21 CFR 207.13,
and 21 CFR 807.65, as applicable.
4. 	How does a 361 HCT/P establishment submit their tissue establishment
registration, and where can an establishment find more information on
how to register and list HCT/Ps?
HCT/P establishments that manufacture 361 HCT/Ps must register and list
electronically under 21 CFR part 1271 using the electronic Human Cell and
Tissue Establishment Registration System (eHCTERS)7 to meet the requirement
for electronic submission of establishment registration and product listing (21
CFR 1271.22). Establishments may request a waiver from the electronic
7 eHCTERS and instructions for use accessible at https://www.fda.gov/vaccines-blood-biologics/biologics-
establishment-registration/tissue-establishment-registration.

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submission requirement as described in 21 CFR 1271.23. HCT/P establishments
may also submit questions about registration to TissueReg@fda.hhs.gov.
5. 	When must new 361 HCT/P establishments register and list their
HCT/Ps?
New establishments must register and submit a list of their 361 HCT/Ps within 5
days after beginning operations (21 CFR 1271.21(a)). The establishment should
also appoint a Reporting Official who will be responsible for registration and
listing updates and/or changes and who will serve as the contact for all
registration-related communication.
6. 	How will a 361 HCT/P establishment know when it is officially registered
with FDA?
FDA considers the establishment to be registered as soon as FDA receives the
registration information submitted in eHCTERS. After FDA processes the
establishment’s registration, FDA will send to the Reporting Official the
Registration Summary Report, which includes the FDA Establishment Identifier
(FEI) number. If an establishment already registered under separate requirements
in 21 CFR parts 207, 6078, and/or 807, the establishment will generally retain the
same FEI number.
When the establishment has submitted their HCT/P manufacturing registration
information to the FDA, the registration status is identified as “Pre-registered” in
eHCTERS until the FEI number is assigned. The establishment may contact FDA
at TissueReg@fda.hhs.gov or access the Public Query Application to determine
the status of their registration.9 The establishment’s status will change to
“registered” after the FEI number has been assigned. An establishment may also
use the Public Query Application to access a list of other 361 HCT/P
establishments that are registered with the FDA.
7. 	Does registration mean an establishment is in compliance?
No. FDA acceptance of an establishment registration and HCT/P listing form
does not constitute a determination that an establishment is in compliance with
applicable rules and regulations or that the HCT/P is licensed or approved by
FDA (21 CFR 1271.27(b)).
8 Establishments that manufacture human blood and blood products and licensed devices must register and list under
21 CFR part 607.
9 Public Query Application accessible at: https://www.fda.gov/vaccines-blood-biologics/biologics-establishment-
registration/human-cell-and-tissue-establishment-registration-hcters-public-query-application.

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8. 	What else will 361 HCT/P establishments have to do after the initial
registration?
Establishments must update their registration annually in December and submit
changes in their HCT/P listing at the time of change or each June or December,
whichever month occurs first after the change (21 CFR 1271.21). Even if there
are no changes or updates to an establishment’s HCT/P listing, the establishment
must still register annually. The establishment’s FEI number and last registration
receipt date are needed to access their registration in eHCTERS. Establishments
can find this information in their most recent Registration Summary Report. FDA
currently sends in November a reminder via email to the Reporting Official
regarding annual registration. If the ownership or location of the establishment
changes or if there is a change in the United States agent’s name, address,
telephone number, or email address, the establishment must submit an amendment
to the registration within 30 calendar days of the change (21 CFR 1271.26).
9. 	What would happen if an establishment required to register under 21
CFR part 207, 807, or 1271 does not register or forgets to submit the
annual registration?
The establishment would be in violation of the applicable registration regulations.
10. Must an individual or company register if it only obtains blood specimens
from HCT/P donors and sends the specimens to a registered
establishment (e.g., a testing laboratory or a recovery establishment) for
testing?
No. If an individual or company is simply obtaining a blood specimen from an
HCT/P donor and sending the blood specimen to a registered testing laboratory or
to a registered recovery establishment for testing, then the individual or company
is not required to register. Obtaining a blood specimen is not considered part of
manufacturing.
11. Must an establishment (laboratory) register if it only performs speciation
of microorganisms already detected in a culture specimen from a 361
HCT/P?
Yes. By definition, the term “manufacture” includes processing, and processing
includes testing for microorganisms (21 CFR 1271.3(e) and (ff)). Testing for
microorganisms generally includes sampling, culturing, and identifying the
microorganisms present in the sample (speciation). FDA is aware that HCT/P
manufacturers use this information in a number of ways, including determining
whether an HCT/P may be further processed and/or distributed. If an
establishment (laboratory) only performs speciation of microorganisms, the
establishment must register because it is performing a processing step (21 CFR
1271.1(b)).

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12. What is the process to inactivate registration if the establishment no
longer manufactures 361 HCT/Ps or has gone out of business?
The Reporting Official of the establishment may inactivate the establishment
registration using eHCTERS.
13. Must a hospital have multiple registrations if it manufactures more than
one type of 361 HCT/P (e.g., hematopoietic stem/progenitor cells,
reproductive cells) or if it performs different manufacturing functions
(e.g., recovery, processing, donor testing)?
Each establishment will generally have only one registration number (FEI
number) for any combination of HCT/P types manufactured and/or manufacturing
functions. An establishment means a place of business under one management, at
one general physical location, that engages in the manufacture of HCT/Ps (21
CFR 1271.3(b)). One general physical location could be reasonably construed to
include separate buildings within close proximity provided that the activities in
them are closely related to the same business enterprise, under the supervision of
the same local management, and capable of being inspected at the same time. For
example, a hospital administrator could facilitate one registration of multiple
laboratories under the same management. However, FDA requires separate
registrations for two or more business enterprises that manufacture 361 HCT/Ps
and are separate legal entities with different management even if both use the
same facility or the same address (see 21 CFR 1271.3(b), 1271.10(b), and
1271.21).
14. Must a hospital be registered if the only functions performed there with
respect to HCT/Ps are surgical removal and temporary storage of
autologous HCT/Ps prior to their implantation?
An establishment that only removes HCT/Ps from an individual and implants
such HCT/Ps into the same individual during the same surgical procedure is not
required to comply with the requirements of 21 CFR part 1271, including
registration and listing (21 CFR 1271.15(b)). For additional information on
FDA’s current thinking on the scope of the exception set forth in 21 CFR
1271.15(b), including the types of procedures that may be considered the same
surgical procedure, see the SSPE Guidance (Ref. 2).
15. Must a hospital register and list with respect to 361 HCT/Ps that it
receives, stores, and routinely shares with other hospitals?
Yes. Hospitals that receive 361 HCT/Ps and make them available for distribution
to other establishments (e.g., hospitals) are performing the manufacturing steps of
storage and distribution and therefore must register and list those 361 HCT/Ps (21
CFR 1271.3(e), 1271.10(b), and 1271.21). An establishment is not required to

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comply with the requirements of 21 CFR part 1271 if the establishment does not
recover, screen, test, process, label, package, or distribute, but only receives or
stores HCT/Ps solely for implantation, transplantation, infusion, or transfer within
its facility (21 CFR 1271.15(d)).
16. Must an establishment be registered if it recovers HCT/Ps for teaching
and nonclinical research purposes only?
No. According to 21 CFR 1271.15(a), if your establishment only recovers HCT/Ps
that are used solely for nonclinical scientific or educational purposes, you are not
required to comply with the requirements of 21 CFR part 1271, including
registration and listing.
DONOR ELIGIBILITY
1. 	What are the donor eligibility (DE) requirements for HCT/Ps?
The DE requirements are outlined in title 21 CFR part 1271, subpart C. A DE
determination is required for all donors of cells or tissue used in HCT/Ps,
recovered on or after May 25, 2005,10 except as provided under 21 CFR 1271.90
and must be based on donor screening and testing for relevant communicable
disease agents and diseases (RCDADs) (21 CFR 1271.45(b)). An HCT/P must
not be implanted, transplanted, infused, or transferred until the donor has been
determined to be eligible, except as provided under 21 CFR 1271.60(d),
1271.65(b), and 1271.90 (21 CFR 1271.45(c)). A DE determination is a
determination of whether a donor is eligible based on the results of donor
screening in accordance with 21 CFR 1271.75 and donor testing in accordance
with 21 CFR 1271.80 and 1271.85 (21 CFR 1271.50(a)).
2. 	Where can an establishment find more information on donor eligibility?
An establishment can find more comprehensive information on DE by accessing
FDA’s “Guidance for Industry: Eligibility Determination for Donors of Human
Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps),” dated August
2007 (2007 DE Guidance) (Ref. 4) and “Guidance for Industry: Certain Human
Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) Recovered
From Donors Who Were Tested For Communicable Diseases Using Pooled
Specimens or Diagnostic Tests,” dated April 2008 (Ref. 5).
10 69 FR 29786 (May 25, 2004).

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FDA has issued guidance documents11 that notified establishments of a new
RCDAD and/or recommended specific donor screening and testing measures,
which serve to supplement recommendations in certain sections of the 2007 DE
Guidance.
CURRENT GOOD TISSUE PRACTICE
1. 	What are current good tissue practice (CGTP) requirements?
CGTP requirements are the requirements in 21 CFR part 1271, subpart C and
subpart D, that govern the methods used in, and the facilities and controls used
for, the manufacture of HCT/Ps, including but not limited to all steps in recovery,
donor screening, donor testing, processing, storage, labeling, packaging, and
distribution (21 CFR 1271.150(a)). The CGTP Guidance (Ref. 3) provides
HCT/P establishments with recommendations for complying with CGTP
requirements under 21 CFR part 1271, subpart D and additional requirements
under subpart E. For additional information on subpart C, refer to the 2007 DE
Guidance (Ref. 4).
2. 	What is the purpose of the CGTP requirements?
The CGTP requirements aim to prevent the introduction, transmission, or spread
of communicable diseases by HCT/Ps by reducing the risk that the HCT/Ps
contain communicable disease agents (e.g., viruses, bacteria, fungi, parasites, and
transmissible spongiform encephalopathy agents), and by preventing
contamination during manufacturing.
3. 	Who must comply with the CGTP requirements if one establishment
engages another establishment (e.g., a contract establishment) to perform
certain steps in manufacture of HCT/Ps, under a contract, agreement, or
other arrangement?
The contract establishment must comply with those CGTP requirements
applicable to the manufacturing step(s) that it performs under a contract,
agreement, or other arrangement (21 CFR 1271.150(c)(1)(ii)). The establishment
that is contracting for outside manufacturing work must ensure that the contract
establishment complies with applicable CGTP requirements before entering into
the contract, agreement, or arrangement (21 CFR 1271.150(c)(1)(iii)). For
further information, see “Guidance for Industry: Compliance with 21 CFR part
1271.150(c)(1) – Manufacturing Arrangements”, dated September 2006 (Ref. 6).
11 All FDA guidance documents related to DE requirements for HCT/Ps may be found at:
https://www.fda.gov/vaccines-blood-biologics/biologics-guidances/tissue-guidances.

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4. 	How does an HCT/P establishment request an exemption or an
alternative to a requirement?
Under 21 CFR 1271.155, an establishment may request an exemption from or
alternative to any requirement in subpart C (Donor Eligibility) or subpart D
(Current Good Tissue Practice) of 21 CFR part 1271. Note that on June 22, 2016,
FDA published a final rule, entitled “Revisions to Exceptions Applicable to
Certain Human Cells, Tissues, and Cellular and Tissue-Based Products” (81 FR
40512, June 22, 2016), which revised 21 CFR part 1271 to clarify that if an
embryo was originally intended for reproductive use for a specific individual or
couple, its subsequent directed or anonymous donation for reproductive use
would not be prohibited under 21 CFR 1271.45(c), even when the applicable
donor eligibility requirements under part 1271, subpart C, are not met (see 21
CFR 1271.90(b)).
You must ordinarily request an exemption or alternative under 21 CFR
1271.155(d) in writing (hardcopy or electronically). However, you may request
an exemption orally if circumstances make it difficult (e.g., there is inadequate
time) to submit your request in writing. You must follow an oral request with an
immediate written request (21 CFR 1271.155(d)). Requests for exemptions or
alternative methods must be submitted to the appropriate Center (21 CFR
1271.155(b)).
As stated in 21 CFR 1271.155(b), the request must be accompanied by supporting
documentation, including all relevant valid scientific data. More information on
the criteria for granting exemptions and alternatives and the supporting
documentation required may be found at: https://www.fda.gov/vaccines-blood-
biologics/tissue-tissue-products/exemptions-and-alternatives.
If the HCT/P is regulated solely under section 361 of the PHS Act and regulations
in part 1271, or as a biological product or medical device regulated by CBER,
requests should be sent to:
Director, Office of Tissues and Advanced Therapies
Center for Biologics Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave
Document Control Center
WO71-G112
Silver Spring, MD 20993-0002
If you have questions concerning these requests, need to orally request an
exemption or alternative, or wish to submit a request electronically, please refer to
the Exemptions and Alternatives website above.

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If the HCT/P is regulated as a medical device by CDRH, the request should be
sent to:
Combination Product Jurisdiction Officer
Center for Devices and Radiological Health
Food and Drug Administration
10903 New Hampshire Ave
Document Control Center
WO66-G609
Silver Spring, MD 20993-0002
If you have questions concerning these requests or need to orally request an
exemption or alternative, please refer to the Exemptions and Alternatives website
above.
5. 	Is an HCT/P establishment required to investigate and report adverse
reactions related to 361 HCT/Ps?
Establishments that make nonreproductive 361 HCT/Ps available for distribution
are required to investigate adverse reactions involving a communicable disease
related to those 361 HCT/Ps (21 CFR 1271.350(a)(1)). In addition, the
establishments must report to FDA such adverse reactions that meet any of the
criteria under 21 CFR 1271.350(a)(1)(i)-(iv). FDA issued a guidance entitled
“Investigating and Reporting Adverse Reactions Related to Human Cells, Tissues,
and Cellular and Tissue-Based Products (HCT/Ps) Regulated Solely under section
361 of the Public Health Service Act and 21 CFR part 1271”, dated March 2016
(Ref. 7) with recommendations for complying with the requirements under 21
CFR part 1271, subparts D and E, for investigating and reporting of complaints of
adverse reactions involving communicable disease in recipients of 361 HCT/Ps.
That guidance provides updated information specific to reporting adverse
reactions related to HCT/Ps, to supplement the general instructions accompanying
the MedWatch mandatory reporting form, Form FDA 3500A, and supplements
section XXII of the CGTP Guidance (Ref. 3).
6. 	Is an HCT/P establishment required to investigate and report deviations
for 361 HCT/Ps?
Establishments that manufacture nonreproductive 361 HCT/Ps are required to
investigate all HCT/P deviations related to distributed 361 HCT/Ps for which they
performed a manufacturing step (21 CFR 1271.350(b)(1)). Under 21 CFR
1271.350(b)(2), the establishment must report to FDA any such HCT/P deviation
relating to the core CGTP requirements defined in 21 CFR 1271.150(b), if the
HCT/P deviation occurred in its facility or in a facility that performed a
manufacturing step for the establishment under contract, agreement, or other
arrangement. FDA issued the guidance, “Deviation Reporting for Human Cells,
Tissues, and Cellular and Tissue-Based Products Regulated Solely Under Section

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13
361 of the Public Health Service Act and 21 CFR Part 1271” dated September
2017 (Ref. 8) to provide establishments that manufacture non-reproductive 361
HCT/Ps, with recommendations and relevant examples for complying with the
requirements under 21 CFR 1271.350(b) to investigate and report HCT/P
deviations.
The guidance also supplements sections V. and XXII. of the CGTP Guidance
(Ref. 3), by providing additional recommendations specific to an establishment’s
responsibilities to investigate HCT/P deviations concerning 361 HCT/Ps under 21
CFR 1271.160(b)(6) and 1271.350(b).
FDA INSPECTION AND ENFORCEMENT OF ESTABLISHMENTS
DESCRIBED IN 21 CFR 1271.10
1. 	What does an FDA inspection involve?
An FDA inspection of an establishment that manufactures 361 HCT/Ps will be
conducted as necessary in the judgment of FDA to determine compliance with the
applicable provisions in 21 CFR part 1271 (21 CFR 1271.400(a)). The FDA
inspection may include, but is not limited to, an assessment of the establishment’s
facilities, equipment, finished and unfinished materials, containers, processes,
HCT/Ps, procedures, labeling, records, files, papers and controls required to be
maintained under 21 CFR part 1271 (21 CFR 1271.400(a)).
FDA will call upon the most responsible person available at the time of the
inspection of the establishment and may question the personnel as necessary to
determine compliance with the provisions of 21 CFR part 1271 (21 CFR
1271.400(c)). FDA representatives may take samples, may review and copy any
records required to be kept under 21 CFR part 1271, and may use other
appropriate means to record evidence of observations during inspections (21 CFR
1271.400(d)).
For reproductive establishments, inspections will be limited to determining
compliance with applicable provisions contained in 21 CFR part 1271, subparts
A, B, and C; and 21 CFR 1271.150(c)(1) and 1271.155 of subpart D (see 21 CFR
1271.150(c)(3) and 1271.330).
As of May 15, 2017, as part of the broader agency Program Alignment initiative,
FDA’s Office of Regulatory Affairs (ORA) implemented a program-based
management structure that aligns staff, including inspection staff, by FDA-
regulated product. This organizational approach replaced a management structure
based on geographic regions. The goal is to improve our public health response
in a way that keeps pace with the acceleration of scientific innovation, global
expansion of markets, and modern legal authorities.12
12 See FDA’s Program Alignment and ORA webpage at https://www.fda.gov/about-fda/office-regulatory-
affairs/program-alignment-and-ora for more details.

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2. 	When will an FDA inspection be performed?
An FDA inspection of an establishment that manufactures 361 HCT/Ps will
ordinarily be performed during regular business hours and may be made with or
without prior notification (21 CFR 1271.400(a)). The frequency of inspection will
be at FDA’s discretion (21 CFR 1271.400(b)).
3. 	What compliance or enforcement actions can FDA take to prevent the
introduction, transmission, or spread of communicable diseases for 361
HCT/Ps?
For 361 HCT/Ps, advisory, administrative and judicial actions that FDA may take
in response to violations of 21 CFR part 1271 include an Untitled Letter; Warning
Letter; Orders of Retention, Recall, Destruction, and/or Cessation of
Manufacturing; and prosecution.
A Warning Letter is a correspondence that notifies regulated industry about
violations that FDA has identified during its inspections or other investigations to
provide an opportunity to take prompt, voluntary corrective action. Typically, a
Warning Letter notifies a responsible individual or establishment that FDA
considers one or more products, practices, processes, or other activities to be in
violation of statutes or their implementing regulations. Warning Letters are only
issued for violations of regulatory significance (i.e., those that may lead to an
enforcement action if the documented violations are not promptly and adequately
corrected). An Untitled Letter is a correspondence with regulated industry that
cites violations that do not meet the threshold of regulatory significance for a
Warning Letter.
Under 21 CFR 1271.440, FDA may issue orders for retention, recall, destruction,
and/or cessation of manufacturing. FDA may take one or more of these actions
upon an agency finding that there are reasonable grounds to believe the following:
(a) an HCT/P is a violative HCT/P because it was manufactured in violation of the
regulations in 21 CFR part 1271 and, therefore, the conditions of manufacture of
the HCT/P do not provide adequate protections against risks of communicable
disease transmission; or (b) the HCT/P is infected or contaminated so as to be a
source of dangerous infection to humans; or (c) an establishment is in violation of
the regulations in 21 CFR part 1271 and, therefore, does not provide adequate
protections against the risks of communicable disease transmission.
FDA may pursue prosecution in certain circumstances, such as when there are
gross, flagrant or intentional violations, fraud, danger to health, or a continued or
repeated course of violative conduct. Because 21 CFR part 1271 was
promulgated pursuant to section 361 of the PHS Act (42 U.S.C. 264), there are
criminal penalties found in 42 U.S.C. 271(a) that may apply: “Any person who
violates any regulation prescribed under [42 U.S.C. 264] . . . shall be punished by
a fine of not more than $1,000 or by imprisonment for not more than one year, or

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both.” However, Title 18 of the United States Code (U.S.C.) contains
superseding penalties provisions for federal crimes. Under 18 U.S.C. 3551, “a
defendant who has been found guilty of an offense described in any Federal
statute” is governed by the sentencing provisions of 18 U.S.C. Chapter 227 (18
USC 3551-3586). Under 18 U.S.C. 3559(a)(6), any federal criminal offense
which carries a possible maximum sentence of one year or less, but more than six
months, is a Class A misdemeanor. The statutory fines for Class A misdemeanor
federal offenses are, for individuals, for a violation resulting in death, not more
than $250,000; otherwise; not more than $100,000 (18 U.S.C. 3571(b)(4) and
(5)). For organizations, including corporations, for a violation resulting in death,
not more than $500,000; otherwise, not more than $200,000 (18 U.S.C.
3571(c)(4) and (5)).
4. 	When would an FDA order for cessation of manufacturing go into
immediate effect?
An FDA order for cessation of manufacturing will go into immediate effect only
when FDA determines that there are reasonable grounds to believe that there is a
danger to health if the establishment continues to manufacture (see 21 CFR
1271.440(a)(3)).
5. 	Are there any exceptions to the enforcement provisions in 21 CFR part
1271, subpart F?
Yes. As described in 21 CFR 1271.440(f), FDA will not issue an order for the
destruction of reproductive tissue, nor will it carry out such destruction itself.
6. 	What are the requirements for 361 HCT/Ps offered for import?
Under 21 CFR 1271.420(a), when an HCT/P (except for certain reproductive
HCT/Ps and peripheral blood stem/progenitor cells as described in 21 CFR
1271(c) and(d)) is offered for import, the importer of record must notify the FDA
Director (or designee) of the district that covers the port of entry before or at the
time of importation and provide sufficient information for FDA to make an
admissibility decision. HCT/Ps offered for import must be held intact by the
importer of record or consignee, under conditions necessary to prevent
transmission of communicable disease, until an admissibility decision is made by
FDA (21 CFR 1271.420(b)). Due to the perishable nature of most HCT/Ps, an
HCT/P may be transported under quarantine to the consignee while FDA is
determining admissibility of the HCT/P (21 CFR 1271.420(b)).
The “FDA Investigations Operations Manual 2021 (IOM)” (Ref. 9) is the primary
operational reference for FDA employees who perform field investigational
activities in support of the agency’s public health mission and has more
information on inspectional and import activities.

Contains Nonbinding Recommendations
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Contains Nonbinding Recommendations
17
7. 	What are the exceptions for 361 HCT/Ps offered for import?
The import provisions in 21 CFR 1271.420 do not apply to reproductive HCT/Ps
regulated solely under section 361 of the PHS Act and the regulations in 21 CFR
part 1271, and donated by a sexually intimate partner of the recipient for
reproductive use (21 CFR 1271.420(c)). In addition, such import provisions do
not apply to peripheral blood stem/progenitor cells regulated solely under section
361 of the PHS Act and the regulations in 21 CFR part 1271, except when
circumstances occur under which such imported peripheral blood stem/progenitor
cells may present an unreasonable risk of communicable disease transmission
indicating the need to review the information referenced in 21 CFR 1271.420(a).
In such circumstances, 21 CFR 1271.420(a) and (b) apply (21 CFR 1271.420(d)).

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III. 	REFERENCES
1. 	Guidance for Industry and Food and Drug Administration Staff: Regulatory
Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products:
Minimal Manipulation and Homologous Use, November 2017 and Corrected July 2020,
available at: https://www.fda.gov/media/109176/download
2. 	Guidance for Industry: Same Surgical Procedure Exception under 21 CFR 1271.15(b):
Questions and Answers Regarding the Scope of the Exception, November 2017, available
at: https://www.fda.gov/media/89920/download
3. 	Guidance for Industry: Current Good Tissue Practice (CGTP) and Additional
Requirements for Manufacturers of Human Cells, Tissues, and Cellular and Tissue-Based
Products (HCT/Ps), December 2011, available at:
https://www.fda.gov/media/82724/download
4. 	Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues,
and Cellular and Tissue-Based Products (HCT/Ps), August 2007, available at:
https://www.fda.gov/media/73072/download
5. 	Guidance for Industry: Certain Human Cells, Tissues, and Cellular and Tissue-Based
Products (HCT/Ps) Recovered From Donors Who Were Tested For Communicable
Diseases Using Pooled Specimens or Diagnostic Tests, April 2008, available at
https://www.fda.gov/media/70696/download
6. 	Guidance for Industry: Compliance with 21 CFR Part 1271.150(c)(1) – Manufacturing
Arrangements”, September 2006, available at:
https://www.fda.gov/media/70696/download
7. 	FDA Guidance: Investigating and Reporting Adverse Reactions Related to Human Cells,
Tissues, and Cellular and Tissue-Based Products (HCT/Ps) Regulated Solely under
Section 361 of the Public Health Service Act and 21 CFR Part 1271, March 2016,
available at: https://www.fda.gov/media/91082/download
8. 	FDA Guidance: Deviation Reporting for Human Cells, Tissues, and Cellular and Tissue-
Based Products Regulated Solely Under Section 361 of the Public Health Service Act and
21 CFR Part 1271, September 2017, available at:
https://www.fda.gov/media/107703/download
9. 	FDA Investigations Operations Manual, 2021, available at:
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-
investigations/inspection-references/investigations-operations-manual