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  Contains Nonbinding Recommendations 
 
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, FDAs guidance documents do not establish legally enforceable responsibilities. 
Instead, guidances describe the Agencys 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 FDAs 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 FDAs 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 FDAs 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 FDAs 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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Contains Nonbinding Recommendations 
 
  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 FDAs 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 FDAs 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 
establishments 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 establishments 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 establishments HCT/P listing, the establishment 
must still register annually.  The establishments 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 agents 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 
FDAs 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 
FDAs 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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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 establishments 
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 establishments 
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, 
FDAs 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 FDAs 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 FDAs 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 agencys public health mission and has more 
information on inspectional and import activities. 
  
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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 
18