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 
 
 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
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/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guid
ances/default.htm. 
 
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 
September 2017 
  Contains Nonbinding Recommendations 
 
Table of Contents 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  HCT/P DEVIATION REPORTING ............................................................................... 4 
A.  What is an HCT/P Deviation? ............................................................................. 4 
B.  Who Must Investigate and Report an HCT/P Deviation? ................................ 4 
C.  What are Some Examples of Who Must Report an HCT/P Deviation? .......... 5 
D.  When Am I Not Required to Submit a Report? ................................................ 8 
E.  What Information Should I Include in an HCT/P Deviation Report? ............ 9 
F.  When Do I Report an HCT/P Deviation? ........................................................... 9 
G.  How and Where Do I Submit a Report for an HCT/P Deviation? ................... 9 
IV.  EXAMPLES OF REPORTABLE HCT/P DEVIATIONS AND NON-
REPORTABLE FINDINGS .......................................................................................... 10 
A.  Donor Eligibility (21 CFR 1271.50) ................................................................... 10 
B.  Donor Screening (21 CFR 1271.75) ................................................................... 12 
C.  Donor Testing (21 CFR 1271.80 and 21 CFR 1271.85) ................................... 13 
D.  Processing and Process Controls (21 CFR 1271.220) ...................................... 15 
E.  Receipt, Predistribution, Shipment, and Distribution (21 CFR 1271.265(a) 
through (d)).......................................................................................................... 16 
V.  CONCLUSION ............................................................................................................... 18 
 
i  Contains Nonbinding Recommendations 
 
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 
 
 
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 
 
We, the Food and Drug Administration (FDA), are issuing this guidance to provide you, 
establishments that manufacture non-reproductive human cells, tissues, and cellular and tissue-
based products (HCT/Ps) that are regulated solely under section 361 of the Public Health Service 
Act (PHS Act) and the regulations under Title 21 of the Code of Federal Regulations (CFR) Part 
1271, with recommendations and relevant examples for complying with the requirements under 
21 CFR 1271.350(b) to investigate and report HCT/P deviations.  The examples provided in this 
guidance have been chosen to illustrate those HCT/P deviations that have been most frequently 
reported to FDAs Center for Biologics Evaluation and Research (CBER).1 
 
This guidance document does not apply to reproductive HCT/Ps2 or to HCT/Ps regulated under 
21 CFR Part 1270 and recovered before May 25, 2005.  Furthermore, this guidance does not 
apply to healthcare professionals who implant, transplant, infuse, or transfer HCT/Ps into 
recipients.3 
 
                                                 
1 See FDAs Annual Report Summaries at 
https://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ReportaProblem/BiologicalProductDeviations/ucm
129757.htm.  
2 See 21 CFR 1271.150(c)(3)). 
3 See 21 CFR 1271.15(d).  However, FDA notes that healthcare professionals have an important role in identifying 
HCT/P deviations and reporting HCT/P deviations to manufacturers of HCT/Ps.  Further, manufacturers may seek to 
obtain additional information from healthcare professionals such as recipient culture reports or recipient clinical 
records when investigating the possible transmission of communicable disease related to HCT/Ps that the 
manufacturer made available for distribution. 
1  Contains Nonbinding Recommendations 
 
This guidance document also does not apply to HCT/Ps that are regulated as drugs, devices, 
and/or biological products under section 351 of the PHS Act and/or the Federal Food, Drug, and 
Cosmetic Act, nor does it apply to investigational HCT/Ps subject to an investigational new drug 
(IND) application or an investigational device exemption (IDE).  This guidance finalizes the 
draft guidance of the same title dated December 2015. 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the FDAs 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 FDAs guidances means that something is suggested or 
recommended, but not required. 
 
 
II.  BACKGROUND 
 
On November 24, 2004, FDA published in the Federal Register the final rule entitled Current 
Good Tissue Practice for Human Cell, Tissue, and Cellular and Tissue-Based Product 
Establishments; Inspection and Enforcement (69 FR 68612).4  This rule, which became 
effective on May 25, 2005, requires HCT/P establishments to follow current good tissue practice 
(CGTP), which governs the methods used in, and the facilities and controls used for, the 
manufacture of HCT/Ps; recordkeeping; and the establishment of a quality program.  The rule 
also established certain core CGTP requirements under 21 CFR 1271.150(b) that are directly 
related to preventing the introduction, transmission, or spread of communicable diseases.  In 
addition, certain requirements in subparts D and E of 21 CFR Part 1271 were limited in their 
applicability to these core CGTP requirements, including the requirement under  
21 CFR 1271.350(b) to report HCT/P deviations to FDA.   
 
An HCT/P is regulated solely under section 361 of the PHS Act and the regulations under  
21 CFR Part 1271 if it meets all of the following criteria under 21 CFR 1271.10(a): 
 
1. The HCT/P is minimally manipulated;  
 
2. The HCT/P is intended for homologous use only, as reflected by the labeling, 
 
advertising, or other indications of the manufacturers objective intent;  
3. The manufacture of the HCT/P does not involve the combination of the cells or 
 
tissues with another article, except for water, crystalloids, or a sterilizing, 
preserving, or storage agent, provided that the addition of water, crystalloids, or 
the sterilizing, preserving, or storage agent does not raise new clinical safety 
concerns with respect to the HCT/P; AND  
                                                 
4 Available at 
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ActsRulesRegulations/T
issueProposedFinalRules/default.htm.   
2  Contains Nonbinding Recommendations 
 
4. Either:   
 
i.  The HCT/P does not have a systemic effect and is not dependent upon the 
metabolic activity of living cells for its primary function; OR  
ii.  The HCT/P has a systemic effect or is dependent upon the metabolic 
activity of living cells for its primary function; AND 
a)  Is for autologous use; 
b)  Is for allogeneic use in a first-degree or second-degree blood 
relative; OR 
c)  Is for reproductive use. 
 
Under 21 CFR 1271.350(b), an establishment that manufactures non-reproductive HCT/Ps5 that 
meet all of the above criteria must investigate all HCT/P deviations related to a distributed 
HCT/P for which the establishment performed a manufacturing step.  Such establishment must 
report, to FDA, within 45 days of the discovery of the event, any such HCT/P deviation relating 
to the core CGTP requirements, if the HCT/P deviation occurred in their facility or in a facility 
that performed a manufacturing step under contract, agreement, or other arrangement.  
 
As noted above, and discussed in more detail in a separate guidance,6 all core CGTP 
requirements found at 21 CFR 1271.150(b) directly relate to preventing the introduction, 
transmission, or spread of communicable diseases by HCT/Ps.  The following are core CGTP 
requirements: 
 
  Donor-eligibility determinations, donor screening, and donor testing  
(21 CFR 1271.50, 1271.75, 1271.80, and 1271.85);  
  Facilities (21 CFR 1271.190(a) and (b));  
  Environmental control (21 CFR 1271.195(a));  
  Equipment (21 CFR 1271.200(a));  
  Supplies and reagents (21 CFR 1271.210(a) and (b));  
  Recovery (21 CFR 1271.215);  
  Processing and process controls (21 CFR 1271.220);  
  Labeling controls (21 CFR 1271.250(a) and (b));  
  Storage (21 CFR 1271.260(a) through (d)); and 
  Receipt, predistribution shipment, and distribution of an HCT/P (21 CFR 1271.265(a) 
through (d)).  
 
Under 21 CFR 1271.150(a), you must follow CGTP requirements to prevent the introduction, 
transmission, or spread of communicable diseases by HCT/Ps (e.g., by ensuring that the HCT/Ps 
do not contain communicable disease agents, that they are not contaminated, and that they do not 
become contaminated during manufacturing).  Communicable diseases include, but are not 
                                                 
5 See 21 CFR 1271.330. 
6 See FDAs 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 
available at 
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/T
issue/UCM285223.pdf. 
3  Contains Nonbinding Recommendations 
 
limited to, those transmitted by viruses, bacteria, fungi, parasites, and transmissible spongiform 
encephalopathy agents.  In addition, under 21 CFR 1271.180, HCT/P establishments must 
establish and maintain procedures appropriate to meet core CGTP requirements.   
 
 
III.  HCT/P DEVIATION REPORTING  
 
A.  What is an HCT/P Deviation? 
 
The term HCT/P deviation is defined in 21 CFR 1271.3(dd) as an event: 
 
1.  That represents a deviation from applicable regulations in  
21 CFR Part 1271 or from applicable standards or established 
specifications that relate to the prevention of communicable disease 
transmission or HCT/P contamination; 
or  
2.  That is an unexpected or unforeseeable event that may relate to the 
transmission or potential transmission of a communicable disease or may 
lead to HCT/P contamination. 
 
B.  Who Must Investigate and Report an HCT/P Deviation? 
 
Under 21 CFR 1271.350(b)(1), an establishment must investigate all HCT/P deviations 
related to a distributed HCT/P for which you performed a manufacturing step.  
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)).  Distribution means any 
conveyance or shipment (including importation and exportation) of an HCT/P that has 
been determined to meet all release criteria, whether or not such conveyance or shipment 
is entirely intrastate.  If an entity does not take physical possession of an HCT/P, the 
entity is not considered a distributor (21 CFR 1271.3(bb)).  
 
Under 21 CFR 1271.350(b)(2), you must report to FDA any such HCT/P deviation 
relating to the core CGTP requirements, if the HCT/P deviation occurred in your facility 
or in a facility that performed a manufacturing step for you under contract, agreement, or 
other arrangement.  We recommend that the HCT/P establishment that makes the HCT/P 
available for distribution be responsible for reporting HCT/P deviations related to 
distributed products to FDA.  Available for distribution means that the HCT/P has been 
determined to meet all release criteria (21 CFR 1271.3(z)).  If the distributing HCT/P 
establishment has notified the contract facility that it has filed a deviation report, FDA 
does not intend to enforce any requirement for the contract facility to submit a second, 
duplicative HCT/P deviation report.  However, the contract facility would be required to 
investigate the deviation in accordance with 21 CFR 1271.350(b)(1) and  
21 CFR 1271.160(b)(6), as also discussed below. 
 
4  Contains Nonbinding Recommendations 
 
Although 21 CFR 1271.350(b)(1) requires you to investigate all HCT/P deviations related 
to a distributed HCT/P for which you performed a manufacturing step, we remind all 
establishments, including contract facilities, that, as described in 21 CFR 1271.160(b)(2), 
a quality program for all establishments involved in manufacturing HCT/Ps must ensure 
that procedures exist for receiving, investigating, evaluating and documenting 
information relating to core CGTP requirements, including complaints, and for sharing 
any information pertaining to the possible contamination of the HCT/P or the potential 
for transmission of a communicable disease by the HCT/P with other establishments and 
consignees.  Complete details regarding other establishments and consignees are 
provided in the provision under 21 CFR 1271.160(b)(2)(i) through (iii).  In addition, we 
remind all establishments, including contract facilities, that 21 CFR 1271.160(b)(6) 
requires establishments to investigate and document HCT/P deviations and trends of 
HCT/P deviations relating to core CGTP requirements and making reports if required 
under 21 CFR 1271.350(b) or other applicable regulations. 
 
C.  What are Some Examples of Who Must Report an HCT/P Deviation? 
 
Because timely and accurate reporting of HCT/P deviations has been of considerable 
interest to industry stakeholders, we explain who is responsible to report an HCT/P 
deviation to FDA based on the following event scenarios: 
 
1.  You are an establishment that has a contract, agreement, or other 
arrangement with another establishment to perform donor screening for you.  
Based on the review of the relevant medical records you received from the 
contract establishment that performed the donor screening, you determined the 
donor to be eligible and distributed the HCT/P.  Subsequently, the contract donor 
screening establishment notified you that during an internal audit, they discovered  
5  Contains Nonbinding Recommendations 
 
that some of the questions related to risk factors for a relevant communicable 
disease agent or disease (RCDAD)7,8,9,10 were not answered when the donor 
medical history interview was conducted.  
 
Who must report:  Under 21 CFR 1271.350(b)(1), you must investigate the 
HCT/P deviation related to a distributed HCT/P.  In addition, under  
21 CFR 1271.160(b)(6), the contract establishment is responsible for investigating 
and documenting the HCT/P deviation and, under 21 CFR 1271.160(b)(2)(ii), 
they are responsible for notifying you of the event and providing details about the 
investigation.  We recommend that, you, the establishment that distributed the 
HCT/P, submit the report required under 21 CFR 1271.350(b)(2) because the 
HCT/P deviation is related to core CGTP requirements (specifically,  
                                                 
7 Under 21 CFR 1271.3(r), relevant communicable disease agent or disease (RCDAD) for non-reproductive 
HCT/Ps includes the following:   
  Human immunodeficiency virus (HIV), types 1 and 2;  
o
  Hepatitis B virus (HBV);  
o
  Hepatitis C virus (HCV);  
o
  Human transmissible spongiform encephalopathy (TSE); including Creutzfeldt-Jakob disease (CJD);  
o
  Human T-lymphotropic virus (HTLV), types I and II (for viable, leukocyte-rich cells and tissues);  
o
  Treponema pallidum (syphilis); 
o
  West Nile virus;  
o
  Sepsis;  
o
  Vaccinia; and 
o
  Zika virus 
o
8 West Nile virus, sepsis, vaccinia, and Zika virus are communicable disease agents or diseases, not specifically 
listed under 21 CFR 1271.3(r)(1), but determined to be relevant communicable disease agents or diseases under  
21 CFR 1271.3(r)(2).  More information regarding these additional relevant communicable disease agents or 
diseases can be found at FDAs Tissue Guidances page at 
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Tissue/defaul
t.htm.  
9 See Donor Screening Recommendations to Reduce the Risk of Transmission of Zika Virus by Human Cells, 
Tissues, and Cellular and Tissue-Based Products; Guidance for Industry, dated March 2016; available at 
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/T
issue/UCM488582.pdf.   
10 See the following guidance documents for recommendations for nucleic acid testing to reduce the risk of West 
Nile virus and Hepatitis B virus, and other screening tests recommended for Treponema pallidum (Syphilis): 
o  Guidance for Industry:  Use of Nucleic Acid Tests to Reduce the Risk of Transmission of West Nile Virus 
from Living Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps), dated 
September 2016; available at 
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Gu
idances/Tissue/UCM372084.pdf;  
o  Guidance for Industry:  Use of Nucleic Acid Tests to Reduce the Risk of Transmission of Hepatitis B 
Virus from Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products, dated August 
2016; available at 
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Gu
idances/UCM516650.pdf; 
Guidance for Industry:  Use of Donor Screening Tests to Test Donors of Human Cells, Tissues and 
Cellular and Tissue-Based Products for Infection with Treponema pallidum (Syphilis), dated September 
2015; available at 
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Gu
idances/Tissue/UCM373311.pdf. 
6  Contains Nonbinding Recommendations 
 
21 CFR 1271.75) and occurred in a facility that performed a manufacturing step 
for you under contract, agreement, or other arrangement.  If you, the distributing 
HCT/P establishment, have notified the contract facility that you have filed a 
deviation report, FDA does not intend to enforce any requirement for the contract 
facility to submit a second, duplicative HCT/P deviation report. 
 
2.  You are an establishment that performs all manufacturing steps for fresh 
skin.  The HCT/P was cultured for microorganisms prior to distribution and 
distributed prior to the availability of the culture results.  After distribution, a 
positive culture result was obtained that did not meet your release criteria 
designed to prevent the introduction, transmission, or spread of communicable 
disease. 
 
Who must report:  Under 21 CFR 1271.350(b)(1), you must investigate an HCT/P 
deviation related to a distributed HCT/P, and under 21 CFR 1271.350(b)(2), you 
must submit a report to FDA because the HCT/P deviation is related to a core 
CGTP requirement (specifically, 21 CFR 1271.265(c)(2)) and occurred in your 
facility. 
  
3.  You are an establishment that determined all release criteria have been 
met for an HCT/P and subsequently distributed the HCT/P to a hospital.  The 
hospital stored the HCT/P in a cold room until needed for one of their patients.  
The cold room in the hospital lost power for a period of time.  The surgeon 
voluntarily notified you that he had decided not to utilize the tissue.  
 
Who must report:  You are not responsible for submitting an HCT/P deviation 
report because the deviation was not related to a manufacturing step you 
performed.  The hospital is not responsible for reporting because they meet the 
exception under 21 CFR 1271.15(d), which states that you are not required to 
comply with the requirements of 21 CFR Part 1271 if you are an establishment 
that 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 your facility.  
  
4.  You are an establishment that has a contract, agreement, or other 
arrangement with another establishment to perform donor testing for you.  After 
receiving negative results from the testing establishment, you determined the 
donor to be eligible and distributed the HCT/P.  Subsequently, the testing 
establishment notifies you that during an internal audit, they discovered testing 
was performed using a diagnostic test kit for communicable disease testing 
instead of an FDA approved test kit for donor screening.  
 
7  Contains Nonbinding Recommendations 
 
Who must report:  Under 21 CFR 1271.350(b)(1), you must investigate the 
HCT/P deviation related to a distributed HCT/P and under  
21 CFR 1271.350(b)(2), you must submit a report to FDA because the HCT/P 
deviation is related to core CGTP requirements (specifically, 21 CFR 1271.80(c)) 
and occurred in a facility that performed a manufacturing step for you under a 
contract, agreement, or other arrangement.  The HCT/P deviation report should 
include all distributed HCT/Ps for which donor testing was performed using a 
diagnostic test kit for communicable disease testing instead of an FDA approved 
test kit for donor screening.  
 
The testing establishment is also required to investigate and document the HCT/P 
deviation under 21 CFR 1271.160(b)(6).  Under 21 CFR 1271.160(b)(2)(ii), they 
are responsible for notifying you, and any other establishments for whom they 
performed testing with respect to the same HCT/P, of the event and providing 
details about the investigation.  If you, the distributing HCT/P establishment, have 
notified the testing establishment that you have filed a deviation report, FDA does 
not intend to enforce any requirement for the testing establishment to submit a 
second, duplicative HCT/P deviation report to FDA.  
 
5.  You are an establishment that independently stores and distributes 
HCT/Ps, meaning you are not under a contract, agreement, or other arrangement 
with another establishment.  You distributed an HCT/P that was stored at a higher 
temperature than your established acceptable temperature limits for storage  
(21 CFR 1271.260(e)), posing a potential risk for contamination.  
 
Who must report:  Under 21 CFR 1271.350(b)(1), you must investigate the 
HCT/P deviation related to a distributed HCT/P and under  
21 CFR 1271.350(b)(2), you must submit a report to FDA because the HCT/P 
deviation is related to a core CGTP requirement (specifically, 21 CFR 
1271.260(b)) and occurred in your facility.  The HCT/P deviation report must 
include all distributed HCT/Ps that were stored at the unacceptable temperature.  
 
D.  When Am I Not Required to Submit a Report? 
 
You are not required to submit a report when: 
 
  The event does not meet the definition of an HCT/P deviation as defined 
in 21 CFR 1271.3(dd). 
  The deviation is not related to a core CGTP requirement as defined in  
21 CFR 1271.150(b). 
  You detected a deviation, so you did not distribute the HCT/P. 
  You detected a deviation and, prior to distribution, you made appropriate 
corrections following appropriate procedures. 
  The deviation is related to an HCT/P not subject to HCT/P deviation 
reporting (e.g., reproductive tissue). 
 
8  Contains Nonbinding Recommendations 
 
E.  What Information Should I Include in an HCT/P Deviation Report? 
 
Under 21 CFR 1271.350(b)(2), each HCT/P deviation report must contain a description 
of the HCT/P deviation, information relevant to the event and the manufacture of the 
HCT/P involved, and information on all follow-up actions that have been or will be taken 
in response to the HCT/P deviation (e.g., recalls). 
 
We recommend that you complete a separate report for each event.  However, if a single 
event involves more than one HCT/P, you only should complete one report listing all 
distributed HCT/Ps affected.  
 
F.  When Do I Report an HCT/P Deviation? 
 
Under 21 CFR 1271.350(b)(3), you must report each HCT/P deviation that relates to a 
core CGTP requirement within 45 days of the discovery of the event.  If the HCT/P 
deviation occurred in a facility that performed a manufacturing step for you under 
contract, agreement, or other arrangement, the time period for reporting will start when 
that contract establishment learned about the event. 
 
G.  How and Where Do I Submit a Report for an HCT/P Deviation? 
 
Under 21 CFR 1271.350(b)(3), you must report each HCT/P deviation on Form FDA 
3486.  We strongly encourage you to submit the report electronically through CBERs 
website (see instructions for using electronic biological product deviations reporting 
(eBPDR) system at 
https://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ReportaProblem/Biolog
icalProductDeviations/ucm134535.htm).  The Form FDA 3486 and instructions for 
completing the form electronically or by mail may be found at 
https://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ReportaProblem/Biolog
icalProductDeviations/default.htm. 
 
You may submit the completed report by mail to: 
 
U.S. Food and Drug Administration 
Center for Biologics Evaluation and Research  
Document Control Center   
10903 New Hampshire Avenue 
Bldg. 71, Rm. G112 
Silver Spring, MD 20993-0002 
 
9  Contains Nonbinding Recommendations 
 
We also remind you that HCT/P establishments are required to report adverse reactions 
under 21 CFR 1271.350(a), and recommendations regarding adverse reaction reporting 
can be found in a separate guidance document.11  If the adverse reaction occurs as a result 
of an HCT/P deviation, you must submit both an adverse reaction report and an HCT/P 
deviation report. 
 
 
IV.  EXAMPLES OF REPORTABLE HCT/P DEVIATIONS AND NON-
REPORTABLE FINDINGS 
 
This guidance provides examples of HCT/P deviations that have been most frequently reported 
to CBER.12  These include deviations to the following core CGTP requirements:   
 
  Donor-eligibility determinations, donor screening, and donor testing  
(21 CFR 1271.50, 1271.75, 1271.80, and 1271.85); 
  Processing and process controls (21 CFR 1271.220); and  
  Receipt, predistribution shipment, and distribution of an HCT/P (21 CFR 1271.265(a) 
through (d)).  
 
However, we remind you that you are required to report HCT/P deviations relating to all core 
CGTP requirements. 
 
Because timely and accurate reporting of HCT/P deviations has been of considerable interest to 
industry stakeholders, we describe examples of both reportable and non-reportable events.  The 
following examples are not all-inclusive and do not represent all variations that may occur.  In all 
examples, the HCT/P was distributed. 
 
A.  Donor Eligibility (21 CFR 1271.50) 
 
1.  What are the core CGTP requirements for donor eligibility?  
 
In accordance with 21 CFR 1271.50(a), if you are the establishment responsible 
for making the donor-eligibility determination, you must determine whether a 
donor is eligible based upon 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.  A responsible person, as defined in 21 CFR 1271.3(t), must determine 
and document the eligibility of a cell or tissue donor. 
 
                                                 
11 See FDAs Guidance for Industry:  MedWatch Form FDA 3500A: Mandatory Reporting of Adverse Reactions 
Related to Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps), dated November 2005; 
available at 
https://www.fda.gov/biologicsbloodvaccines/safetyavailability/reportaproblem/ucm153082.htm. 
12 See FDAs Annual Report Summaries available at 
https://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ReportaProblem/BiologicalProductDeviations/ucm
129757.htm.  
10  Contains Nonbinding Recommendations 
 
Under 21 CFR 1271.50(b), a donor is eligible only if: 
a.  Donor screening in accordance with 21 CFR 1271.75 shows that the donor 
is free from risk factors for, and clinical evidence of, infection due to 
RCDADs, and is free from communicable disease risks associated with 
xenotransplantation; and 
b.  Test results for RCDADs in accordance with 21 CFR 1271.80 and 
1271.85 are negative or nonreactive, except as provided in  
21 CFR 1271.80(d)(1). 
 
2.  What are some examples of reportable HCT/P deviations related to donor-
eligibility determination?   
 
The following are examples of reportable HCT/P deviations which you 
discovered after you had already distributed an HCT/P that was obtained from a 
donor who was initially, but incorrectly, determined to be eligible.  In each 
example, the donor information was overlooked and the donor was erroneously 
determined to be eligible.   
 
a.  A donor tested positive for an RCDAD.  This information was provided 
by the testing laboratory and recorded in the relevant medical records.  
b.  A donor engaged in behavior related to risk factors for RCDADs (e.g., sex 
in exchange for drugs) in the preceding five years. 
c.  A donors final autopsy report documented that death was due to sepsis 
and the donors medical records documented a medical diagnosis of 
sepsis. 
 
3.  What are some examples of non-reportable findings related to donor-
eligibility? 
 
a.  A donor had a localized infection or positive blood culture, but no 
documented clinical evidence or diagnosis of sepsis. 
b.  A donor had a history of a disease not considered an RCDAD. (e.g., 
Chagas, malaria, Lyme disease, or lymphoma). 
c.  The autopsy report stated that the cause of death was unknown or 
undetermined. 
d.  A donor of an HCT/P intended for allogeneic use in a first-degree or 
second-degree blood relative was determined ineligible due to behavior 
related to risk factors for RCDADs. Limited uses of the product are not 
prohibited (21 CFR 1271.65(b)(1)).  
e.  A donor was determined ineligible due to behavior related to risk factors 
for RCDADs; however, there was a documented urgent medical need (as 
defined in 21 CFR 1271.3(u)) for the use of the HCT/P.  Limited uses of 
the product are not prohibited (21 CFR 1271.65(b)(1)). 
 
11  Contains Nonbinding Recommendations 
 
B.  Donor Screening (21 CFR 1271.75) 
 
1.  What are the core CGTP requirements for donor screening? 
 
Under 21 CFR 1271.75(a), you must screen a cell or tissue donor by reviewing 
relevant medical records for risk factors for, and clinical evidence of, RCDADs; 
and communicable disease risks associated with xenotransplantation, unless an 
exception identified in 21 CFR 1271.90(a) applies.  For donors of viable, 
leukocyte-rich cells or tissue, you must also screen for HTLV  
(21 CFR 1271.75(b)).  
 
2.  What are some examples of reportable HCT/P deviations related to donor 
screening? 
 
The following are examples of reportable HCT/P deviations which you 
discovered after you had already distributed an HCT/P that was obtained from a 
donor who was initially, but incorrectly, determined to be eligible.  In each 
example, the donor information was overlooked and the donor was erroneously 
determined to be eligible. 
 
a.  Donor screening for evidence of RCDADs was not performed or 
documented, or the screening was incomplete.  Relevant medical records 
were not reviewed. 
 
b.  During an audit (or review) of the electronically recorded donor 
medical/social history interview, you discover that responses to questions 
related to a risk factor for RCDADs were incorrectly reflected on the 
written donor medical/social history questionnaire. 
 
c.  New information was discovered during a quality audit of the relevant 
medical records, and a re-evaluation indicated there was a risk associated 
with human TSE, which is an RCDAD. 
 
3.  What are some examples of non-reportable findings related to donor 
screening? 
 
a.  Donor medical/social history questionnaire was missing responses or had 
discrepant responses (e.g., yes and no) to questions that were not related to 
the prevention or spread of communicable disease transmission or HCT/P 
contamination (e.g., donor had history of heart disease).  
b.  Donor screening was not performed for an autologous HCT/P donor which 
was required by your establishments standard operating procedures 
(SOPs) but not required by FDA according to 21 CFR 1271.90. 
 
12  Contains Nonbinding Recommendations 
 
C.  Donor Testing (21 CFR 1271.80 and 21 CFR 1271.85) 
 
1.  What are the core CGTP requirements for donor testing for RCDADs? 
 
Under 21 CFR 1271.80: 
 
a.  You must test a donor specimen for evidence of infection due to RCDADs 
and other required communicable disease agents (e.g., cytomegalovirus 
(CMV)) as specified in 21 CFR 1271.85.13, 14, 15 
b.  You must collect the donor specimen for testing at the time of recovery of 
cells or tissue from the donor; or up to 7 days before or after recovery, 
with specific exceptions.16 
c.  You must use appropriate FDA-licensed, approved or cleared donor 
screening tests, in accordance with the manufacturers instructions, if such 
tests are available.17,18 
i.  You must use a donor screening test specifically labeled for 
cadaveric specimens instead of a more generally labeled donor 
screening test when applicable and when available. 
ii.  Testing must be performed by a lab either certified to perform such 
testing under the Clinical Laboratory Improvement Amendments 
of 1988 (CLIA) or the equivalent as determined by the Centers for 
Medicare and Medicaid Services.19 
d.  You must determine certain donors to be ineligible, as specified in  
21 CFR 1271.80(d). 
 
                                                 
13 See 21 CFR 1271.85 for specific requirements pertaining to what donor testing is required for different types of 
cells and tissues. 
14 A listing of the recommended tests for RCDADs and other required communicable disease agents (e.g., CMV) 
can also be found in FDAs Guidance for Industry:  Eligibility Determination for Donors of Human Cells, Tissues, 
and Cellular and Tissue-Based Products (HCT/Ps), dated August 2007; available at 
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/T
issue/ucm091345.pdf.   
15 See footnote 10.  
16 See 21 CFR 1271.80(b) for specific exceptions. 
17 See complete list of current FDA-licensed donor screening tests for RCDADs available at 
https://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/TissueSafety/ucm095440.htm.  
18 CLIA categorized FDA approved/cleared tests can be found on FDAs public CLIA database: 
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCLIA/search.cfm. 
19 Information about the CLIA program is available at the website:  
https://www.cms.gov/Regulations-and-Guidance/Legislation/CLIA/downloads/HowObtainCLIACertificate.pdf. 
13  Contains Nonbinding Recommendations 
 
2.  What are some examples of reportable HCT/P deviations related to donor 
testing? 
 
The following are examples of reportable HCT/P deviations which you 
discovered after you had already distributed an HCT/P that was obtained from a 
donor who was initially, but incorrectly, determined to be eligible.  In each 
example, the donor information was overlooked and the donor was erroneously 
determined to be eligible. 
 
a.  Required donor testing was not performed for all RCDADs and other 
communicable disease agents (e.g., CMV).   
b.  Required donor testing for RCDADs was not performed in accordance 
with the manufacturers test kit instructions. 
c.  Required donor testing for RCDADs was performed with an unacceptable 
donor specimen, in that the specimen was collected 10 days before the 
recovery of musculoskeletal HCT/Ps. 
d.  A donor specimen was incorrectly filtered or collected in an expired 
sample collection tube (containing anticoagulant) and, as such, did not 
meet the requirements according to the manufacturers instructions. 
e.  A donor of viable, leukocyte-rich HCT/Ps was not tested for HTLV or 
CMV. 
f.  A donor specimen was tested using a diagnostic test kit instead of an 
FDA-licensed, approved, or cleared donor screening test. 
g.  A donor was either not evaluated for, incorrectly evaluated for, or the 
evaluation was not documented for plasma dilution. 
 
3.  What are some examples of non-reportable findings related to donor 
testing? 
 
a.  Required donor testing for RCDADs was performed by a facility that was 
not registered with FDA, but was CLIA certified, and licensed test kits 
were used for testing.20 
b.  Donor testing for RCDADs was incorrectly performed on a specimen from 
an autologous donor.  Donor eligibility determination, donor screening 
and donor testing of autologous donors is not required  
(21 CFR 1271.90(a)(1)). 
c.  Although the donor testing sample was collected within the required 
timeframe, an incorrect sample collection time was documented on an 
infectious disease testing result report. 
d.  A donor eligibility determination for a RCDAD was made according to 
existing recommendations, however subsequently the recommendations 
                                                 
20 If you are a domestic or foreign establishment that manufactures an HCT/P described in 21 CFR 1271.10(a), you 
must register with FDA (see 21 CFR 1271.10(b)(1)).  Section 1271.10(b)(1) is not a core CGTP requirement so the 
example does not meet the criteria to report the finding as an HCT/P deviation.  However, failure to register with 
FDA would be in violation of 21 CFR 1271.10(b)(1). 
14  Contains Nonbinding Recommendations 
 
changed in a manner that the donor eligibility would now be inconsistent 
with the recommendation. For example, a donor-eligibility determination 
for an RCDAD that was tied to date of recovery and/or geographic 
location of recovery or travel of the donor such as the case described for 
WNV or Zika virus.  
 
D.  Processing and Process Controls (21 CFR 1271.220) 
 
1.  What are the core CGTP requirements for HCT/P processing? 
 
If you are an establishment that processes HCT/Ps, you must process each HCT/P 
in a way that does not cause contamination or cross-contamination during 
processing, and that prevents the introduction, transmission, or spread of 
communicable disease through the use of the HCT/P (21 CFR 1271.220(a)). 
 
Human cells or tissues from two or more donors must not be pooled (placed in 
physical contact or mixed in a single receptacle) during manufacturing  
(21 CFR 1271.220(b)). 
 
Furthermore, under 21 CFR 1271.220(c), you must ensure that specified 
requirements, consistent with the general requirements of 21 CFR 1271.220(a), 
for in-process controls are met, and that each in-process HCT/P is controlled until 
the required inspection and tests or other verification activities have been 
completed, or until necessary approvals are received and documented.  Sampling 
of in-process HCT/Ps must be representative of the material to be evaluated  
(21 CFR 1271.220(c)). 
 
For dura mater, when there is a published validated process that reduces the risk 
of TSE, you must use this process (or an equivalent process that you have 
validated), unless following this process adversely affects the clinical utility of the 
dura mater (21 CFR 1271.220(d)(1)).  When you use a published validated 
process, you must verify such a process in your establishment  
(21 CFR 1271.220(d)(2)).21 
 
                                                 
21 Additional guidance and recommendations for other HCT/Ps (e.g., musculoskeletal HCT/Ps) are provided in 
Section XIII. Processing and Process Controls ( 1271.220) in FDAs 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; available at  
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/T
issue/UCM285223.pdf. 
15  Contains Nonbinding Recommendations 
 
2.  What are some examples of reportable HCT/P deviations related to 
processing and process controls22?   
 
a.  Musculoskeletal HCT/Ps from two or more donors were pooled during 
manufacturing.  
b.  In-process control procedures were not followed.  
c.  During in-process testing, the HCT/P was cultured for microorganisms; 
however the sample was not representative of the material being 
evaluated. 
 
3.  What are some examples of non-reportable findings related to processing 
and process controls? 
 
a.  During a processing step of freezing an HCT/P, a different concentration 
of dimethyl sulfoxide (DMSO) was used than was specified in the HCT/P 
establishments SOP. 
b.  Processing steps were performed according to the HCT/P establishments 
SOP, but were not documented concurrently with performance of each 
step (21 CFR 1271.270(a)). 
 
E.  Receipt, Predistribution, Shipment, and Distribution (21 CFR 1271.265(a) 
through (d))  
 
1.  What are the core CGTP requirements for HCT/P receipt, predistribution, 
shipment, and distribution? 
 
Under 21 CFR 1271.265(a), you must evaluate each incoming HCT/P for the 
presence and significance of microorganisms and inspect for damage and 
contamination.  You also must determine whether to accept, reject, or place in 
quarantine each incoming HCT/P, based upon pre-established criteria designed to 
prevent communicable disease transmission. 
 
Under 21 CFR 1271.265(b), if you ship an HCT/P within your establishment or 
between establishments (e.g., procurer to processor) and the HCT/P is not 
available for distribution as described in 21 CFR 1271.265(c) (known as 
predistribution shipment), you must first determine and document whether pre-
established criteria designed to prevent communicable disease transmission have 
been met, and you must ship the HCT/P in quarantine.  
 
Under 21 CFR 1271.265(c)(1), before making an HCT/P available for 
distribution, you must review manufacturing records (such as records from the 
donor-eligibility determination, recovery, processing, and storage) and tracking 
records pertaining to the HCT/P, and, on the basis of that record review, you must 
                                                 
22 If there is a deviation in a process control operation that you perform only periodically, you should report all 
potentially affected products distributed since the last successful operation. 
16  Contains Nonbinding Recommendations 
 
verify and document that the release criteria have been met.  Also, a responsible 
person must document and date the determination that an HCT/P is available for 
distribution (21 CFR 1271.265(c)(1)).  Moreover, under 21 CFR 1271.265(c)(2), 
you must not make available for distribution an HCT/P that is:  
 
  in quarantine;  
  contaminated;23  
  received from a donor who has been determined to be ineligible or a 
donor with an incomplete donor-eligibility determination (except as 
provided in 21 CFR 1271.60, 1271.65, and 1271.90); or  
  otherwise does not meet release criteria designed to prevent 
communicable disease transmission. 
 
Under 21 CFR 1271.265(c)(3), if you make a departure from a procedure that is 
relevant to preventing risks of communicable disease transmission, you must not 
make an HCT/P manufactured under the departure available for distribution, 
unless a responsible person has determined that the departure does not increase 
the risk of communicable disease through the use of the HCT/P.  You must record 
and justify any departure from a procedure at the time of its occurrence. 
 
For each type of HCT/P, you must establish appropriate shipping conditions to be 
maintained during transit (21 CFR 1271.265(d)). 
 
2.  What are some examples of reportable HCT/P deviations related to 
receipt, predistribution, shipment, and distribution?   
 
a.  A responsible person did not review and verify tracking records, and did 
not document that the release criteria had been met for an HCT/P that was 
distributed. 
b.  A quarantined HCT/P that was not available for distribution because it 
was recovered from an ineligible donor was distributed.24 
c.  A contaminated HCT/P was distributed (e.g., an HCT/P with a positive 
bacterial or fungal culture result was distributed). 
 
                                                 
23 Note that skin cultures taken post-processing may be positive for non-pathogenic normal flora but this is not 
considered contamination.  See section XVIII.E. of FDAs 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; available at 
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/T
issue/UCM285223.pdf. 
24 In certain situations, there are limited uses of an HCT/P from an ineligible donor.  See 21 CFR 1271.65(b) and (c). 
17  Contains Nonbinding Recommendations 
 
3.  What are some examples of non-reportable findings related to receipt, 
predistribution, shipment, and distribution?  
 
a.  An incorrect HCT/P (e.g., the establishment distributed a properly labeled 
bone instead of tendon, which was ordered) was distributed, but the 
HCT/P had met all the release criteria and was acceptable for distribution.  
b.  A summary of records is missing the date and time of the release of the 
HCT/P. 
c.  An HCT/P was acceptable at the time of distribution.  The consignee 
caused the sterility to be compromised by improperly opening or 
mishandling the product. 
 
 
V.  CONCLUSION 
 
This guidance describes scenarios to illustrate who must investigate and report HCT/P 
deviations, what must be reported, and when such reports must be submitted to FDA under  
21 CFR Part 1271.  Because timely and accurate reporting of HCT/P deviations has been of 
considerable interest to industry stakeholders, we provide examples of both reportable and non-
reportable events.  The examples provided in this guidance have been chosen to illustrate the 
most frequently reported HCT/P deviations that have historically been submitted to CBER.  They 
are not all-inclusive and do not represent all variations that may occur.  For these reasons, FDA 
encourages communication and inquiries to ensure proper reporting of HCT/P deviations.  If you 
have questions, you should contact CBERs Biological Product Deviation Reporting team in the 
Office of Compliance and Biologics Quality (OCBQ) via telephone at 240-402-9160 or email at 
hctp_deviations@fda.hhs.gov. 
 
18