Manufacturing Considerations for Licensed and Investigational Cellular and Gene Therapy Products During COVID-19 Public Health Emergency: Guidance for Industry

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Contains Nonbinding Recommendations
Manufacturing Considerations for
Licensed and Investigational Cellular
and Gene Therapy Products During
COVID-19 Public Health Emergency
Guidance for Industry
January 2021
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research

Contains Nonbinding Recommendations
Preface
Public Comment
This guidance is being issued to address the Coronavirus Disease 2019 (COVID-19) public
health emergency. This guidance is being implemented without prior public comment because
the Food and Drug Administration (FDA or Agency) has determined that prior public
participation for this guidance is not feasible or appropriate (see section 701(h)(1)(C) of the
Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 371(h)(1)(C)) and 21 CFR
10.115(g)(2)). This guidance document is being implemented immediately, but it remains
subject to comment in accordance with the Agency’s good guidance practices.
Comments may be submitted at any time for Agency consideration. Submit written comments to
the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852. Submit electronic comments to https://www.regulations.gov.
All comments should be identified with the docket number FDA-2020-D-1137 and complete title
of the guidance in the request.
Additional Copies
Additional copies are available from the FDA webpage titled “COVID-19-Related Guidance
Documents for Industry, FDA Staff, and Other Stakeholders,” available at
https://www.fda.gov/emergency-preparedness-and-response/mcm-issues/covid-19-related-
guidance-documents-industry-fda-staff-and-other-stakeholders, the FDA webpage titled “Search
for FDA Guidance Documents,” available at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents, and the FDA webpage titled “Biologics Guidances”
available at https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-
information-biologics/biologics-guidances. You may also send an email to ocod@fda.hhs.gov to
receive an additional copy of the guidance. Please include the docket number FDA-2020-D-
1137 and complete title of the guidance in the request.
Questions
For questions about this document, contact the Office of Communication, Outreach and
Development (OCOD) by email at ocod@fda.hhs.gov or at 800-835-4709 or 240-402-8010.

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Table of Contents
I. 	INTRODUCTION ................................................................................................................... 1
II. 	BACKGROUND ...................................................................................................................... 2
III. 	RISK ASSESSMENT AND MITIGATION IN PRODUCT MANUFACTURING .......... 3
IV. 	ADDITIONAL RESOURCES ................................................................................................ 5
V. 	REFERENCES ........................................................................................................................ 5

Contains Nonbinding Recommendations
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Manufacturing Considerations for
Licensed and Investigational Cellular
and Gene Therapy Products During
COVID-19 Public Health Emergency
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
FDA plays a critical role in protecting the United States from threats such as emerging infectious
diseases, including the Coronavirus Disease 2019 (COVID-19) pandemic. FDA is committed to
providing timely guidance to support response efforts to this pandemic.
FDA is issuing this guidance to provide manufacturers of licensed and investigational cellular
therapy and gene therapy (CGT) products with risk-based recommendations to minimize
potential transmission of the novel coronavirus, severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2). This guidance is intended to supplement the recommendations to drug and
biological product manufacturers provided in FDA’s “Good Manufacturing Practice
Considerations for Responding to COVID-19 Infection in Employees in Drug and Biological
Products Manufacturing; Guidance for Industry” issued in June 2020 (Ref. 1) (June 2020 GMP
Guidance). The recommendations in this guidance specifically consider the source material
(cells and/or tissues) recovered from donors and how the CGT product will be manufactured
(e.g., cell expansion in culture, viral reduction steps, formulation).
The scope of this guidance applies to CGT products regulated by FDA, Center for Biologics
Evaluation and Research (CBER) as biological products under section 351(i) of the Public
Health Service Act (PHS Act) (42 U.S.C. 262) and as drugs under section 505 of the Federal
Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355).1 	This guidance does not apply to
those human cells, tissues, and cellular- or tissue-based products (HCT/Ps) regulated solely
1 Many of the recommendations in this guidance may apply to combination products that are under the primary
jurisdiction of CBER’s Office of Tissues and Advanced Therapies (OTAT) (such combination products would
consist of a biological product combined with a drug and/or a device).

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under section 361 of the PHS Act (42 U.S.C. 264), as described in Title 21 of the Code of
Federal Regulations (CFR) Part 1271 (21 CFR Part 1271), or regulated as medical devices under
the FD&C Act.
The recommendations in this guidance are intended to remain in effect only for the duration of
the public health emergency related to COVID-19 declared by the Secretary of Health and
Human Services (HHS) on January 31, 2020, effective January 27, 2020, including any renewals
made by the HHS Secretary in accordance with section 319(a)(2) of the PHS Act (42 U.S.C.
247d(a)(2)).
Given this public health emergency, and as discussed in the Notice in the Federal Register of
March 25, 2020 (85 FR 16949), titled “Process for Making Available Guidance Documents
Related to Coronavirus Disease 2019,” available at https://www.govinfo.gov/content/pkg/FR-
2020-03-25/pdf/2020-06222.pdf, this guidance is being implemented without prior public
comment because FDA has determined that prior public participation for this guidance is not
feasible or appropriate (see section 701(h)(1)(C) of the FD&C Act and 21 CFR 10.115(g)(2)).
This guidance document is being implemented immediately, but it remains subject to comment
in accordance with the Agency’s good guidance practices.
The contents of this document do not have the force and effect of law and are not meant to bind
the public in any way, unless specifically incorporated into a contract. This document is intended
only to provide clarity to the public regarding existing requirements under the law. FDA
guidance documents, including this guidance, should be viewed only as recommendations,
unless specific regulatory or statutory requirements are cited. The use of the word should in FDA
guidances means that something is suggested or recommended, but not required.
II. 	BACKGROUND
There is currently an outbreak of respiratory disease caused by a novel coronavirus. The virus
has been named “SARS-CoV-2” and the disease it causes has been named COVID-19. On
January 31, 2020, HHS issued a declaration of a public health emergency related to COVID-19
and mobilized the Operating Divisions of HHS.2 In addition, on March 13, 2020, the President
declared a national emergency in response to COVID-19.3
Respiratory viruses, in general, are not known to be transmitted by implantation, transplantation,
infusion, or transfer of HCT/Ps. FDA is not aware of any CGT products that have been
contaminated with SARS-CoV-2 or of information indicating transmission of SARS-CoV-2 via
these products. However, as noted in FDA’s June 2020 GMP Guidance, (Ref. 1), SARS-CoV-2
is a novel coronavirus and, to ensure compliance with current good manufacturing practice
(CGMP) requirements, CGT manufacturers are expected to evaluate whether it poses new risks in
the context of their specific products, facilities, processes, and manufacturing controls. FDA also
2 Secretary of HHS Alex M. Azar, Determination that a Public Health Emergency Exists (originally issued Jan. 31,
2020, and subsequently renewed), available at
https://www.phe.gov/emergency/news/healthactions/phe/Pages/default.aspx.
3 President Donald J. Trump, Proclamation on Declaring a National Emergency Concerning the Novel Coronavirus
Disease (COVID-19) Outbreak (Mar. 13, 2020), available at https://www.whitehouse.gov/presidential-
actions/proclamation-declaring-national-emergency-concerning-novel-coronavirus-disease-covid-19-outbreak/.

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posted COVID-19 considerations for HCT/P establishments in general.4 Additional concerns
specific to establishments that manufacture CGT products may involve the potential for the
unintended expansion of SARS-CoV-2 in autologous or allogeneic infected cells or tissues
during the manufacturing process (e.g., during cell culture) resulting in a final product with
amplified SARS-CoV-2 viral load.
III. 	RISK ASSESSMENT AND MITIGATION IN PRODUCT MANUFACTURING
During this COVID-19 public health emergency, CGT manufacturers should review CGMP
requirements and recommendations related to facility and equipment cleaning and sanitation and
other controls that ensure materials, active pharmaceutical ingredients (APIs), components, in-
process materials, drug product containers and closures, and drug products are safe and meet
their quality requirements.5 In light of SARS-CoV-2, FDA recommends that CGT product
manufacturers perform a risk assessment that identifies, evaluates, and mitigates factors that may
allow for transmission of SARS-CoV-2 by CGT products. A description of the risk assessment
and mitigation strategies should be included in the appropriate submission to FDA (e.g.,
investigational new drug application (IND), biologics license application (BLA), or master file).
In accordance with quality risk management principles,6 drug manufacturers are expected to
prevent or mitigate potential adverse effects on the safety and quality of their products. To
minimize the risk of SARS-CoV-2 transmission through CGT products, considerations include,
but are not limited to, the assessment of donors, cellular and tissue source materials,
manufacturing processes, manufacturing facility control, product testing, and the number of
subjects that can be treated with the product. For example, an allogeneic product that is
manufactured using a newly established cell bank and/or may be used to treat a large number of
subjects or patients, would be associated with a higher infection risk than an autologous product.
A. 	Donor Assessment
Routine screening measures are already established for evaluating clinical evidence of
infection in allogeneic HCT/P donors. Manufacturers of CGT products derived from
HCT/Ps must determine and document the eligibility of a cell or tissue donor (21 CFR
1271.50). FDA recommends routine screening measures be considered for autologous
HCT/P donors, due to the potential for expansion of SARS-CoV-2 during the
manufacturing process. Based on limited information available at this time, we
recommend that manufacturers consider whether, in the 28 days prior to HCT/P
recovery, the allogeneic or autologous donor:
4 See section III.A of this guidance and Updated Information for Human Cell, Tissue, or Cellular or Tissue-based
Product (HCT/P) Establishments Regarding the COVID-19 Pandemic dated January 4, 2021 available at
https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/updated-information-human-cell-tissue-
or-cellular-or-tissue-based-product-hctp-establishments.
5 For example, other relevant CGMPs include but are not limited to 21 CFR 211.56, 21 CFR 211.67, 21 CFR
211.113, and 21 CFR 211.80. See also ICH Q7, section IV., Buildings and Facilities (4), section V.B., Equipment
Maintenance and Cleaning (5.2), and section VII., Materials Management (7).
6 See the ICH guidance for industry Q9 Quality Risk Management (June 2006).

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1. 	cared for, lived with, or otherwise had close contact with individuals
diagnosed with or suspected of having COVID-19 infection; or
2. 	had been diagnosed with or suspected of having COVID-19 infection; or
3. 	had a positive test result from a diagnostic test approved, cleared, or
authorized by FDA for SARS-CoV-2 but never developed symptoms.
FDA does not recommend using laboratory tests to screen asymptomatic HCT/P donors
for SARS-CoV-2 at this time because SARS-CoV-2 has not been declared a relevant
communicable disease agent and disease under 21 CFR 1271.3(r). However, if a
manufacturer is considering incorporating donor testing for SARS-CoV-2 as a risk
mitigation strategy for manufacturing a CGT product, then viral tests (molecular or
antigen) approved, cleared, or authorized by the FDA7 should be used to diagnose current
infection. Additional information is available from the Centers for Disease Control and
Prevention (CDC).8
At this time, FDA recommends that establishments not screen for or defer HCT/P donors
who have been vaccinated against COVID-19 with non-replicating, inactivated, or RNA-
based COVID-19 vaccines.
B. 	Cellular or Tissue Source Material
Manufacturers should consider the known characteristics of coronaviruses as well as the
ability of SARS-CoV-2 to infect and replicate in the source cells and tissues, as
documented in extensive and evolving literature regarding tissue tropism of SARS-CoV-
2. In addition, manufacturers should consider whether SARS-CoV-2 can infect and
propagate in cells or tissues during certain manufacturing processes (e.g., cell/tissue
culture). Manufacturers should also consider the risk of infection of the specific organ
system (e.g., respiratory system vs. central nervous system) from which the donor cells or
tissues are derived. FDA recommends that manufacturers provide scientific justification
and literature references to support their overall risk assessment and proposed risk
mitigation strategy.
C. 	Manufacturing
In order to minimize the potential for contamination of CGT products with SARS-CoV-
2, unintended expansion of SARS-CoV-2, and transmission of SARS-CoV-2 to facility
personnel during manufacturing, manufacturers should consider starting materials,
manufacturing processes used to control viral spread (e.g., cell expansion in culture, viral
reduction steps, producer cell lines, controls for open systems), and contamination risk
during manufacturing. Of note, SARS-CoV-2 has been shown to be capable of infecting
and replicating in cells commonly used for vector production (e.g., HEK293 and Vero
cells) (Refs. 2 and 3). Further, to ensure compliance with CGMP requirements, CGT
product manufacturers must ensure that employees practice good sanitation and health
habits, in accordance with 21 CFR 211.28(b), 21 CFR 600.10(c) and are expected to
7 See Coronavirus Disease 2019 (COVID-19) Emergency Use Authorizations for Medical Devices - In Vitro
Diagnostics EUAs.
8 See CDC Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens for COVID-19.

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prevent or mitigate potential adverse effects on the safety and quality of drugs from an
infected or potentially infected employee engaged in drug manufacturing (Ref. 1).
D. 	Material Testing
At this time, FDA does not have specific recommendations for testing HCT/P source
material, cell banks, in-process intermediates, final CGT products, or other relevant raw
materials for SARS-CoV-2. However, manufacturers may include such testing as a risk
mitigation strategy based on their assessment of potential risk.
To ensure compliance with CGMP requirements, CGT product manufacturers must
ensure that all evaluations of the production controls (including risk assessments to
determine if drug safety or quality were adversely affected), as well as any follow-up and
changes, are approved by the manufacturer’s quality unit and documented within the
manufacturer’s quality management system, in accordance with 21 CFR 211.22 and 21
CFR 211.100 (see also 21 CFR 211.113). CGT manufacturers should be aware that
under section 501(a)(2) of the FD&C Act, a drug that is not manufactured, processed,
packed, or held in conformity with CGMP to assure that the drug meets certain quality
and purity standards is considered adulterated.
IV. 	ADDITIONAL RESOURCES
For further information, visit the following webpage:
• 	FDA: Coronavirus Disease 2019 (COVID-19) (https://www.fda.gov/emergency-
preparedness-and-response/counterterrorism-and-emerging-threats/coronavirus-disease-
2019-covid-19).
V. 	REFERENCES
1. 	Good Manufacturing Practice Considerations for Responding to COVID-19 Infection in
Employees in Drug and Biological Products Manufacturing, Guidance for Industry, June
2020, https://www.fda.gov/media/139299/download.
2. 	Yamamoto, N., et al., Nelfinavir inhibits replication of severe acute respiratory syndrome
coronavirus 2 in vitro. bioRxiv, 2020: p. 2020.04.06.026476.
3. 	Zang, R., et al., TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human
small intestinal enterocytes. Sci Immunol, 2020. 5(47).