70998 Federal Register / Vol. 88, No. 197 / Friday, October 13, 2023 / Notices 

1https://www.selectagents.gov/sat/list.htm. 

2https://www.bis.doc.gov/index.php/regulations/ 

commerce-control-list-ccl. 

ANDAs, and BLAs for certain CMC 

attributes for ophthalmic drug products. 

This draft guidance is being issued 

consistent with FDA’s good guidance 

practices regulation (21 CFR 10.115). 

The draft guidance, when finalized, will 

represent the current thinking of FDA 

on ‘‘Quality Considerations for Topical 

Ophthalmic Drug Products.’’ 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. 

II. Paperwork Reduction Act of 1995 

While this guidance contains no 

collection of information, it does refer to 

previously approved FDA collections of 

information. The previously approved 

collections of information are subject to 

review by the Office of Management and 

Budget (OMB) under the Paperwork 

Reduction Act of 1995 (PRA) (44 U.S.C. 

3501–3521). The collections of 

information in 21 CFR parts 314 and 

601 have been approved under OMB 

control numbers 0910–0001 and 0910– 

0338, respectively. The collections of 

information in 21 CFR parts 210 and 

211 have been approved under OMB 

control number 0910–0139. 

III. Electronic Access 

Persons with access to the internet 

may obtain the draft guidance at https:// 

www.fda.gov/drugs/guidancecompliance-regulatory-information/ 

guidances-drugs, https://www.fda.gov/ 

regulatory-information/search-fdaguidance-documents, or https://

www.regulations.gov. 

Dated: October 10, 2023. 

Lauren K. Roth, 

Associate Commissioner for Policy. 

[FR Doc. 2023–22650 Filed 10–12–23; 8:45 am] 

BILLING CODE 4164–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Screening Framework Guidance for 

Providers and Users of Synthetic 

Nucleic Acids 

AGENCY: Administration for Strategic 

Preparedness and Response (ASPR), 

Department of Health and Human 

Services (HHS). 

ACTION: Notice. 

SUMMARY: The Administration for 

Strategic Preparedness and Response is 

issuing this screening framework 

guidance, which sets forth baseline 

standards for the gene and genome 

synthesis industry, as well as best 

practices for all entities involved in the 

provision, use, and transfer of synthetic 

nucleic acids, regarding screening 

orders and recipients and maintaining 

records. In addition, this guidance seeks 

to encourage best practices to address 

biosecurity concerns associated with the 

potential misuse of synthetic nucleic 

acids in order to bypass existing 

regulatory controls and commit 

unlawful acts. 

FOR FURTHER INFORMATION CONTACT: C. 

Matthew Sharkey, Administration for 

Strategic Preparedness and Response, 

Department of Health and Human 

Services, 400 7th St. SW, Washington, 

DC 20024; 202–868–9224, 

syndnaguidance@hhs.gov. 

SUPPLEMENTARY INFORMATION: A request 

for public comments on the issues 

covered in this Notice was published in 

the Federal Register (85 FR 52611 [Aug. 

26, 2020]; 85 FR 69630 [Nov. 3, 2020], 

Review and Revision of the Screening 

Framework Guidance for Providers of 

Synthetic Double-Stranded DNA) with a 

comment period of more than 120 days. 

Following consideration of the 

comments received in response to this 

Notice, HHS issued proposed draft 

revised guidance as a Federal Register 

Notice (87 FR 25495 [Apr. 29, 2022], 

Screening Framework Guidance for 

Providers and Users of Synthetic 

Oligonucleotides) and solicited 

additional comments for a period of 60 

days. This Guidance was drafted 

through a deliberative interagency 

process to address the topics raised in 

public comments received in response 

to these prior Notices as well as other 

considerations. Responses received from 

these prior Notices and summaries of 

updates contained in this Guidance are 

available for public review at the 

following website https://aspr.hhs.gov/ 

legal/synna. 

Screening Framework Guidance for 

Providers and Users of Synthetic 

Nucleic Acids 

I. Introduction 

Synthetic biology is an 

interdisciplinary field that focuses on 

the design and fabrication of novel 

biological components and systems as 

well as the redesign and fabrication of 

existing biological systems. Modern 

biotechnologies have made the 

conversion of different types of nucleic 

acids possible (e.g., RNA to DNA), and 

longer genomic sequences can now be 

constructed from very short nucleic 

acids with higher fidelity. Additionally, 

synthetic biology is not limited to 

naturally derived genetic material. 

Thus, this scientific field has the 

potential to generate existing or novel 

components, systems, or organisms 

directly, using only genetic sequence 

data. 

Advances in nucleic acid synthesis 

technology and the open-source 

availability of genetic sequence data 

have significantly contributed to 

discovery and innovation in areas such 

as health and agriculture research and 

development. However, there are 

concerns among the scientific 

community, the nucleic acid synthesis 

industry, the U.S. government, and the 

public that individuals with ill intent 

could exploit biotechnology for harmful 

purposes. The U.S. government has 

acted to minimize risks to public health, 

agriculture, plants, animals, animal or 

plant products, and the environment 

due to biological pathogens and toxins. 

For instance, it has issued the Federal 

Select Agent Regulations, which 

regulate a subset of microbial organisms 

and toxins determined to have the 

potential to pose a severe threat to 

public health and safety, animal health, 

plant health, animal or plant products, 

or the environment. These regulations 

are administered jointly by the CDC, 

Division of Select Agents and Toxins 

and the Animal and Plant Health 

Inspection Service, Division of 

Agricultural Select Agents and Toxins, 

through the Federal Select Agent 

Program (FSAP),1 which sets forth 

requirements for the possession, use, 

and transfer of biological select agents 

and toxins. A second layer of regulation 

is provided by the Bureau of Industry 

and Security (BIS) Export 

Administration Regulations’ Commerce 

Control List (CCL),2 which identifies 

agents and genetic sequences that 

require licenses before export from the 

United States. However, these regulated 

pathogens and toxins do not represent 

the entirety of the potential risks to 

public health, agriculture, plants, 

animals, animal or plant products, or 

the environment that could arise from 

the misuse of synthetic nucleic acids. 

Non-regulated pathogens and toxins, as 

well as other novel types of nucleic acid 

sequences, may also pose significant 

risks if they are misused. To minimize 

these risks, a shift is needed from 

relying solely on lists of regulated 

pathogens and toxins to also assessing 

the risks associated with other nucleic 

acid sequences that may contribute to 

pathogenicity or harm if introduced into 

new genetic frameworks (i.e., Sequences 

of Concern [SOCs]). Also, modern 

molecular biological techniques allow 

the conversion between different types 

of nucleic acids (e.g., RNA to DNA, and 


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3 75 FR 62820 (Oct. 13, 2010). 

4https://www.ncbi.nlm.nih.gov/genbank/. 

5https://www.cdc.gov/labs/BMBL.html. 

6https://www.who.int/publications/i/item/

9789240011311. 

7https://www.who.int/publications/i/item/

9789240056107. 

vice versa), so it has become necessary 

to treat all types of synthetic genetic 

materials with equal care. Additionally, 

benchtop nucleic acid synthesis 

equipment is increasingly common in 

modern laboratories, which changes the 

commercial landscape for synthetic 

nucleic acids. These advances and 

others motivated the U.S. government to 

review and revise the 2010 Screening 

Framework Guidance for Providers of 

Synthetic Double-Stranded DNA.3

Individuals with no legitimate, bona 

fide, and peaceful purpose should be 

prevented from accessing genetic 

materials that could contribute to 

pathogenicity or toxicity, even when 

those materials do not contain 

sequences from FSAP- or CCL-listed 

pathogens or toxins, and nucleic acid 

synthesis equipment. Purchasing or 

synthesizing nucleic acids could enable 

individuals without a legitimate and 

peaceful purpose to possess genetic 

material that would pose risks if 

misused. Synthetic nucleic acids 

ordered from Providers can be used to 

synthesize pathogens de novo or may be 

used to modify non-pathogenic strains 

or create higher risk pathogens or 

toxins. Nucleic acid synthesis has 

removed the need to directly access the 

naturally occurring agents or naturally 

occurring genetic material from these 

agents for those who may wish to do 

harm with them. The potential 

availability of high-risk agents has 

thereby been greatly expanded due to 

this changing commercial landscape. 

The Screening Framework Guidance for 

Providers and Users of Synthetic 

Nucleic Acids (Guidance) reaffirms the 

recommendation to screen for genetic 

sequences from regulated organisms and 

toxins but also recognizes that screening 

should evolve to encompass all 

sequences that are recognized to 

contribute to pathogenicity or toxicity as 

information regarding these sequences 

and their verified functions and 

improved screening methods become 

available (or as feasible). 

This Guidance is intended to assist all 

entities involved in the provision and 

use of synthetic nucleic acids in 

establishing and operating a screening 

framework for synthetic nucleic acid 

orders, including mechanisms to 

identify sequences designed to 

circumvent lists of regulated organisms 

or toxins or sequences that are not Best 

Matches to any sequences in GenBank.4

This Guidance sets forth recommended 

baseline standards for the nucleic acid 

synthesis industry (Providers) and for 

Manufacturers of benchtop nucleic acid 

synthesis devices, as well as best 

practices for Customers of synthetic 

nucleic acids (i.e., institutions, Principal 

Users, End Users, and Third-Party 

Vendors) regarding screening orders for 

SOCs. In addition, this Guidance seeks 

to encourage best practices to address 

biosecurity concerns associated with the 

potential misuse of synthetic nucleic 

acids to bypass existing regulatory 

controls. 

This Guidance recommends that (1) 

upon receiving an order for synthetic 

nucleic acids, Providers and Third-Party 

Vendors perform sequence screening, 

verify the identity of their Customers, 

and follow up to verify the legitimacy of 

the order when SOCs are identified; (2) 

institutions, Third-Party Vendors, 

Principal Users, and End Users keep 

records of synthetic nucleic acid orders 

containing SOCs; (3) institutions and/or 

Principal Users record any transfers 

involving synthetic nucleic acids 

containing SOCs beyond the Principal 

User and manage those transfers 

responsibly to limit the possibility of 

misuse; and (4) Manufacturers only 

distribute equipment capable of 

synthesizing nucleic acids containing 

SOCs to Customers whose legitimacy 

has been verified and implement 

mechanisms to track legitimate use of 

their equipment. 

If sequence screening identifies SOCs, 

Providers should perform further 

validation steps and follow-up 

screening of the Customer to verify the 

legitimacy of the order. Open 

communication between Customers and 

Providers will facilitate the screening 

and validation of orders that contain 

SOCs. Institutions, Principal Users, or 

End Users are best positioned to know 

if they are ordering SOCs and are 

encouraged to provide information with 

their order to preemptively demonstrate 

legitimacy of the order when they are 

aware that it contains SOCs. Providers 

can facilitate this information-sharing 

by including a mechanism for selfreporting and verification of legitimacy 

in their ordering process. If follow-up 

screening does not resolve concerns 

about the order, or if there is reason to 

believe a customer may intentionally or 

inadvertently violate U.S. laws or 

regulations, Providers should not fulfill 

the order and should contact designated 

entities within the U.S. government (i.e., 

U.S. Department of Commerce, Federal 

Bureau of Investigation [FBI]) for further 

information and assistance. 

This Guidance also provides 

recommendations regarding proper 

records retention protocols and 

sequence screening methodologies. 

Additionally, this Guidance 

recommends that institutions, Principal 

Users, and End Users develop and 

follow best practices in biosafety, 

biosecurity, and responsible conduct 

regarding the possession, use, and 

transfer of SOCs. Institutional policies 

and procedures already in place for safe 

possession, use, and transfer of these 

materials, as well as federal and 

international guidance, such as HHS’s 

Centers for Disease Control and 

Prevention (CDC) and National 

Institutes of Health’s Biosafety in 

Microbiological & Biomedical 

Laboratories (BMBL),5 the World Health 

Organization’s Laboratory Biosafety 

Manual,6 and Global Guidance 

Framework for the Responsible Use of 

the Life Sciences: Mitigating Biorisks 

and Governing Dual-Use Research 7

should be used wherever possible to 

complement the measures suggested in 

this Guidance to maximize safe and 

secure practices while seeking to 

minimize the burden on legitimate life 

science research. 

II. Definitions 

The following definitions are 

applicable for the purpose of this 

Guidance: 

Customer: The individual or entity 

(such as an institution) that orders or 

requests synthetic nucleic acids from a 

Provider, or that purchases synthesis 

equipment from a Manufacturer. 

Principal User: The individual who 

originates an order or request for 

synthetic nucleic acids or synthesizes 

nucleic acids and oversees the use of 

ordered or synthesized nucleic acids in 

the laboratory. The Principal User may 

also be the End User. 

End User: The individual who 

possesses and uses synthetic nucleic 

acids that they have received from a 

Customer, Principal User, or another 

End User. 

Provider: The entity that synthesizes 

and distributes synthetic nucleic acids 

to a customer. A Provider is understood 

to be synthesizing nucleic acids as a 

transactional service, rather than a 

research scientist collaborating with a 

colleague (for such transfers between 

collaborators, see End User in this 

section of the Guidance). 

Third-Party Vendor: An entity that 

orders synthetic nucleic acids from 

Providers and sells them or their 

constructs, with or without 

reformulation, or resells benchtop 

equipment for synthesizing nucleic 

acids. 


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8Pathogenicity or toxicity that threatens public 

health, agriculture, plants, animals, animal or plant 

products, or the environment. SOCs include 

sequences for which a direct and harmful impact 

on a host has been verified based on published 

experimental data; and, where experimental data do 

not exist, based on homology to a sequence 

encoding a verified function. 

9Organizations should define and document their 

criteria for determining whether a sequence is of 

concern. In order to ensure compliance with the 

FSAP and CCL regulations, sequences of concern 

should include sequences derived from their listed 

agents—except when they are also found in 

unregulated agents. 

10https://www.bis.doc.gov/index.php/ 

documents/just-licensing-forms/803-bis-711- 

statement-by-ultimate-consignee-and-purchaser-1/ 

file. 

11Open Researcher and Contributor Identifier 

(https://orcid.org/). 

Manufacturer: An entity that 

produces and sells benchtop equipment 

for synthesizing nucleic acids. 

Manufacturers may provide equipment 

to individuals, entities, Principal Users, 

or Third-Party Vendors. 

Sequence of Concern (SOC): A 

nucleotide sequence that is a Best Match 

(see the SEQUENCE SCREENING 

METHODOLOGY section of this 

Guidance) to a sequence of federally 

regulated agents (i.e., the Biological 

Select Agents and Toxins List, or the 

CCL), except when the sequence is also 

found in an unregulated organism or 

toxin. As soon as it is practical to do so, 

it is also recommended that sequences 

known to contribute to pathogenicity or 

toxicity, even when not derived from or 

encoding regulated biological agents, be 

treated as SOCs.8 Follow-up customer 

screening to verify legitimacy should 

take place when a SOC is identified (see 

Verifying Legitimacy in this section of 

the Guidance).9

Synthetic Nucleic Acids Subject to 

Screening: At a minimum, DNA or RNA, 

single- or double-stranded, 200 

nucleotides (nt) or longer should be 

screened for SOCs. This Guidance 

recommends that this length for 

screening be decreased to 50 nt within 

three years of the issuance of the 

Guidance, and that all entities consider 

the potential for shorter nucleotides to 

be assembled into SOCs when multiple 

synthetic nucleic acids are ordered by 

the same Customer in a bulk order or for 

multiple orders over time (see the 

SEQUENCE SCREENING 

METHODOLOGY section of this 

Guidance). 

Benchtop Nucleic Acid Synthesis 

Equipment: Benchtop nucleic acid 

synthesis equipment sold by 

Manufacturers that is intended to be 

used to synthesize nucleic acids for use 

within a research laboratory or within 

an institution. While this nucleic acid 

synthesis equipment may not be small 

enough to be placed on a benchtop (e.g., 

it sits on the laboratory floor), it is still 

considered benchtop equipment if it is 

sold with the intent that it will be used 

by researchers individually or in a core 

facility in an institution. 

Verifying Legitimacy: Review of 

information that would allow Providers, 

Manufacturers, Principal Users, or End 

Users to authenticate the recipient of 

synthetic nucleic acids containing SOCs 

or benchtop nucleic acid synthesis 

equipment as a legitimate member of the 

scientific community. Information such 

as proposed end-use of the order, 

institutional or corporate affiliation (if 

applicable), the name of a biosafety 

officer (if available), documentation of 

internal review and approval of the 

research, evidence provided by the 

recipient’s Responsible Official that the 

recipient is registered with FSAP 1 or 

Statement by Ultimate Consignee and 

Purchaser (i.e., a completed BIS–711 

form 10) (if applicable), or other 

evidence of a legitimate research or 

training program (e.g., publication 

history, researcher persistent identifiers 

such as Open Researcher and 

Contributor Identifier [ORCID],11

business licenses, grant numbers, 

research plan) or other legitimate use 

(e.g., diagnostic test development or 

manufacture) may be helpful for such 

verification. In Verifying Legitimacy, 

providers should avoid the violation of 

personal privacy. Providers should 

focus on professional not personal 

information, except for personal 

information that is necessary to 

establish a unique individual user 

identity to authenticate each recipient. 

III. Goals and Scope of the Guidance 

Goals: This Guidance has three 

parallel goals. A primary goal is to 

minimize the risk that individuals 

without a legitimate need or individuals 

with malicious intent will use nucleic 

acid synthesis technologies to obtain 

organisms for which possession, use, 

and transfer is regulated by FSAP and 

CCL.1 2 Another goal is to limit the 

potential for individuals with malicious 

intent to use synthetic nucleic acids to 

create high-risk pathogens or toxins 

using nucleic acid sequences from 

unregulated organisms. A third goal is 

to minimize disruption of legitimate 

research, commerce, and educational 

activities. 

Scope: The Guidance pertains to the 

sale or transfer of all types of synthetic 

nucleic acids, i.e., DNA and RNA, 

whether single- or double-stranded. The 

Guidance recommends that Providers 

develop and/or consult a database of 

known SOCs to determine if the 

purchase or transfer includes SOCs. It 

also recommends methods that aim to 

ensure the legitimacy of Customers, 

Principal Users, and End Users of 

synthetic nucleic acids. The Guidance 

also aims to ensure that entities 

maintain records of transfers for 

synthetic nucleic acids containing 

SOCs. 

The Guidance was developed to align 

with Providers’ and Customers’ existing 

protocols and business practices, to be 

implemented without unnecessary cost, 

and to minimize any negative impacts 

on the conduct of research and business 

operations. Where practical to do so, 

entities can use existing business 

practices to verify the legitimacy of 

Principal Users and End Users and to 

track the transfer of materials containing 

SOCs. Many Providers have already 

instituted measures to address these 

concerns. The ongoing development of 

best practices in this area is 

commendable and encouraged, 

particularly considering the continued 

advances in nucleic acid sequencing 

and synthesis technologies. 

IV. Recommendations for Providers, 

Users, Institutions, and Manufacturers 

This Guidance encourages the 

establishment of mechanisms that aim 

to ensure that Customers, Principal 

Users, and End Users ordering SOCs are 

legitimate. It also recommends that 

Manufacturers install safeguards in 

nucleic acid synthesis equipment that 

aim to ensure only legitimate Customers 

can synthesize SOCs. This Guidance 

encourages entities transferring 

synthetic nucleic acids containing SOCs 

(i.e., the Third-Party Vendor, Principal 

User, End User, or institution) to know 

to whom they are transferring and to 

conduct screening to verify that the 

recipients have a legitimate, bona fide, 

and peaceful purpose to use the 

synthetic nucleic acids. This Guidance 

recommends that the Customers who 

place these orders use responsible 

business practices to maintain records 

of transfers. 

Principal Users and End Users are 

best positioned to understand the nature 

of their synthetic nucleic acids and 

oversee and shepherd their responsible 

use. Principal Users and End Users may 

also transfer these synthetic nucleic 

acids to other End Users, such as 

colleagues, and certain 

recommendations are made for this case 

in this Guidance. Principal Users and 

End Users are encouraged to streamline 

the screening of their synthetic nucleic 

acid orders by providing verification of 

their legitimacy to Providers and ThirdParty Vendors, if they know that their 

order contains SOCs. 


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12Providers and Third-Party Vendors are 

encouraged to follow the ISA/IEC 27032:2012 & 

ISO/IEC 62443 standards for cybersecurity and 

information security. 

13Here, verifiability means the ability to confirm 

that: every prospective sequence has been screened 

for SOCs against an up-to-date database, and 

screening is up to date and performant; when users 

input sequences of concern, this is flagged and 

reported in real time; and attempts to tamper with 

the device to avoid screening are flagged and 

reported in real time. 

14Manufacturers are encouraged to follow the 

ISO/IEC 27032:2012 & ISO ISA/IEC 62443 standards 

for cybersecurity and information security. 

Information described in the Verifying 

Legitimacy definition will be helpful to 

the Provider or Third-Party Vendor of 

the synthetic nucleic acids in Verifying 

Legitimacy. Preemptively providing this 

information is likely to limit the time 

and expense for Providers in fulfilling 

these orders in a manner that ensures 

safety and security. 

Providers and Third-Party Vendors of 

synthetic nucleic acids are encouraged 

to do the following in this context: 

• Know and document to whom they 

are distributing a product. 

• Know if the product that they are 

synthesizing and/or distributing 

contains identified SOCs. 

• Notify Customers and Principal 

Users when their order contains SOCs. 

• Implement adequate security and 

cybersecurity measures to protect the 

intellectual property and identity of 

Customers.12

• Do not fulfill the order and report 

an order to the FBI when follow-up 

screening does not resolve concerns. 

• Archive the following information 

for orders containing SOCs for at least 

three years: Customer information 

(point-of-contact name, organization, 

address, email, and phone number), 

order sequence information (nucleotide 

sequences ordered, vector used), and 

order information (date placed and 

shipped, shipping address, receiver 

name). Archive this information for 

longer (e.g., eight years) if it does not 

pose an undue burden on business 

operations. 

Customers, Principal Users, and End 

Users of synthetic nucleic acids are 

encouraged to develop best practices in 

five main areas in this context: 

• Customers, Principal Users, and 

End Users who know that their 

synthetic nucleic acid order contains 

SOCs are encouraged to preemptively 

provide information that will assist the 

Provider or Third-Party Vendor in 

verifying their legitimacy. 

• Customers, Principal Users, and 

End Users are encouraged to only 

transfer synthetic nucleic acids 

containing SOCs to verified individuals 

with a legitimate use for these synthetic 

nucleic acids. 

• Customers, Principal Users, and 

End Users are also encouraged to 

maintain records of these transfers and 

to communicate them to their biosafety 

officer, or equivalent, using the 

responsible business practices in place 

in their organizations. 

• Principal Users and End Users are 

encouraged to record transfers of 

synthetic nucleic acids containing SOCs 

to any other individuals not listed in the 

original order through a Material 

Transfer Agreement (MTA), a contract 

that governs the transfer of materials 

between entities for use in research, or 

another sample tracking process. 

Principal Users, End Users, and 

institutions are encouraged to retain 

records of SOC transfers for at least 

three years, or longer (e.g., eight years) 

if it does not pose an undue burden on 

their operations. Business practices 

already in place at institutions may be 

used to fulfill this recommendation. 

• Institutions with in-house nucleic 

acid synthesis capabilities, including 

synthesis equipment, are also 

encouraged to apply these 

recommendations for use or transfers of 

synthetic nucleic acids containing 

SOCs. 

Manufacturers of benchtop nucleic 

acid synthesis equipment, Customers 

using the equipment, and institutions 

where the equipment is used are 

encouraged to consider these areas for 

developing best practices: 

• Manufacturers should screen all 

Customers purchasing benchtop nucleic 

acid synthesizers to validate customer 

legitimacy and that the equipment is 

appropriate for their needs. 

Manufacturers should only provide 

nucleic acid synthesizers to Customers 

that have mechanisms in place that aim 

to ensure that the devices are only 

operated by legitimate users. 

• Institutions should aim to ensure, 

as soon as it is possible to do so, that 

benchtop nucleic acid synthesizers— 

including those that were acquired prior 

to this Guidance—are only accessed by 

users with a legitimate need, such as 

through validated user accounts. If this 

equipment is housed in a core facility 

for an institution, or in other cases when 

the equipment is being operated by an 

authorized user on the behalf of another 

individual, then the institution should 

aim to ensure that the legitimacy of the 

individual receiving any synthetic 

nucleic acids containing SOCs from the 

authorized user or core facility is also 

verified. If misuse or unauthorized 

access to benchtop nucleic acid 

synthesizers with the intent of obtaining 

SOCs is suspected, institutions should 

notify their FBI Field Office Weapons of 

Mass Destruction (WMD) Coordinator. 

• Manufacturers whose benchtop 

nucleic acid synthesizers require the use 

of proprietary and sole-use reagents (i.e., 

reagents that can only be obtained from 

the manufacturer of their devices and do 

not have common applications other 

than the operation of their devices) 

should screen Customers purchasing 

those reagents to verify their legitimacy, 

even when they were not screened 

when obtaining their nucleic acid 

synthesizer (i.e., when they acquired 

their device prior to the issuance of this 

Guidance). 

• Manufacturers and their Customers 

should implement mechanisms to track 

legitimate use of their equipment, 

including when it is potentially 

transferred to a new Principal User or 

End User during the lifecycle of these 

equipment (see the definition of 

Verifying Legitimacy for criteria to 

verify the legitimacy of a User). 

Manufacturers may use methods not 

prescribed within this Guidance to 

achieve this recommendation, such as 

by having a closed loop system in which 

operation of their devices relies upon 

obtaining reagents only available from 

the Manufacturers (who establish the 

legitimacy of Customers whenever they 

obtain these reagents), asking Customers 

to report the transfer of their benchtop 

synthesizers to new users, or requiring 

new user accounts to be verified by the 

Manufacturer as legitimate. 

• Manufacturers should integrate into 

benchtop nucleic acid synthesizers the 

capability to screen sequences for SOCs 

and to authenticate legitimate users. 

This level of screening should be on par 

with the SOC screening best practices 

recommended for Providers in this 

Guidance, including screening against 

SOC databases, when available, that are 

updated regularly as new SOCs are 

identified as a required step before 

synthesizing the sequence, in a 

verifiable manner.13 Manufacturers 

should implement this recommendation 

using measures that ensure 

cybersecurity considerations are 

addressed to guard against malign use 

and to protect both the intellectual 

property and identity of users.14

• Manufacturers should not store 

databases of SOCs that include 

sequences from unregulated pathogens 

or toxins on the device itself in an 

unencrypted manner or a manner that 

could allow users to extract the 

database. The aggregation of all 

sequences that contribute to 

pathogenicity or toxicity poses a 

biosecurity risk that may endanger 

public health, agriculture, plants, 

animals, animal or plant products, or 


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15https://blast.ncbi.nlm.nih.gov/Blast.cgi. 

the environment if disclosed to entities 

or individuals with malintent. 

• Manufacturers should consider 

using cryptographic methods of 

screening that protect the contents of 

the order from disclosure. 

• Manufacturers are encouraged to 

include mechanisms to ensure the 

integrity of the synthesis process to 

prevent circumvention of the SOC 

screening methodology through 

physical or logical manipulation of the 

devices or reagents. 

• Manufacturers are also encouraged 

to include a data logging function to 

maintain a record of the nucleic acids 

synthesized on their equipment. 

• Manufacturers are encouraged to 

formulate a reference architecture 

prescribing guidance for the secure 

implementation, configuration, and 

operation of devices. 

V. Sequence Screening Methodology 

Providers should screen orders to 

determine whether they contain SOCs. 

Appropriate sequence screening 

software should be selected by 

Providers of synthetic nucleic acids. 

This Guidance recommends that 

Providers use either Best Match with a 

local sequence alignment technique 

(such as the Basic Local Alignment 

Search Tool [BLAST] family of tools 15) 

or another screening approach that they 

assess to be equivalent or superior to the 

Best Match approach. Providers are 

encouraged to determine whether 

synthetic nucleic acid orders contain 

sequences that are Best Matches over 

the appropriate windows to any SOC. 

By using the Best Match approach, the 

sequence with the greatest percent 

identity over each 66 amino acid or 200 

nt window (or within three years of the 

publication of this Guidance, over each 

16 amino acid or 50 nt window), in all 

six reading frames, should be 

considered the Best Match, regardless of 

the statistical significance or percent 

identity. The Best Match approach is 

intended to minimize the number of 

sequence hits due to sequences that are 

shared among both SOCs and non-SOCs. 

Some synthetic nucleic acid orders 

may be appropriate for screening even if 

all components of the order are nucleic 

acids shorter than the screening window 

length. In some cases, orders of short 

nucleic acids may be intended to 

construct longer nucleic acids that 

themselves may constitute SOCs. To 

minimize the risk of this scenario, this 

Guidance encourages screening all 

sequences ordered by an individual 

customer, using a short sequence 

alignment software package. If the 

resulting ungapped alignment of any 

constituents of a customer’s order is a 

Best Match to any SOC, and if these 

sequences are constructed to allow their 

ligation to form these SOCs (i.e., 

overlaps are present to support the 

construction of a larger nucleic acid, 

which itself is a SOC), Providers should 

consider those orders as containing 

SOCs and perform standard follow-up 

Customer screening to establish 

legitimacy (see Verifying Legitimacy in 

the DEFINITIONS section of the 

Guidance). 

These sequence screening 

recommendations do not preclude the 

use by Providers of a curated database 

of sequences that may directly 

contribute to pathogenicity or toxicity to 

identify SOCs. This Guidance 

recognizes that a database of known 

sequences that contribute to 

pathogenicity and toxicity in humans, 

animals, and plants, and that have a 

direct and harmful impact on a host, 

may not yet exist or may not yet be fully 

developed and encourages industry 

consortia and/or any other interested 

parties in the continued development of 

such a database for screening SOCs— 

provided that measures are taken to 

prevent such a database from being 

misused. These measures should 

include establishing a security office, 

security protocols, and a personnel 

reliability program—based on a risk 

assessment—to guide selection, 

implementation, and monitoring of 

cybersecurity and information security 

capabilities and protection. These 

measures should aim to ensure database 

confidentiality and integrity (including 

user access controls and sequence 

encryption, both in transit and at rest) 

and compliance with applicable laws 

such that data on SOCs are protected 

against unauthorized access, 

exfiltration, or other use. Providers may 

also choose to use other screening 

approaches that they assess to be 

equivalent or superior to the Best Match 

approach or supplement it, including a 

customized database or approaches that 

evaluate the biological risk associated 

with sequences from unregulated agents 

(i.e., not FSAP- or CCL-listed pathogens 

or toxins). This Guidance encourages 

the continued development of best 

practices to address risks associated 

with nucleic acid synthesis 

technologies. 

Providers, Third-Party Vendors, and 

professional consortia are encouraged to 

develop secure mechanisms—designed 

to respect privacy, security, commercial, 

intellectual property, and other 

concerns—to detect SOCs that may be 

broken up among multiple Providers or 

Vendors, or among multiple orders at a 

single Provider or Vendor over a period 

of time, to evade screening. 

In addition, Providers may wish to 

consider developing solutions for 

determining which sequences from 

pathogens should not cause concern 

(i.e., pass list of genes that pose no 

pathogenic or toxicity risk). 

VI. Customer Screening 

In addition to verifying the Customer 

identity for all orders, Verifying 

Legitimacy of Customers and Users is 

recommended when orders contain 

SOCs, and for orders of nucleic acid 

synthesis equipment. Customers and 

Users are encouraged to streamline the 

Customer screening process by 

providing verification of their 

legitimacy when submitting an order 

containing SOCs. Information described 

in the definition of Verifying Legitimacy 

may be helpful for such verification (See 

also Red Flags for Verifying Legitimacy 

in the Companion Guide to Assist in 

Implementing the Recommendations of 

the Screening Framework Guidance for 

Providers and Users of Synthetic 

Nucleic Acids). 

This Guidance encourages Customers 

and Principal Users to also Verify 

Legitimacy of End Users receiving 

SOCs. Records of such verification and 

transfer can be created and maintained 

by using business practices that 

document such transfers (e.g., MTAs). 

The Principal User is best positioned to 

determine the legitimacy of any End 

User to whom SOCs are transferred. 

Keeping a record of such transfers 

should not cause undue burden on the 

essential research carried out across the 

biotechnology enterprise and may 

therefore entail only a minor adaptation 

of responsible business practices 

already in place. This Guidance does 

not include recommendations for 

reporting transfers to new End Users 

back to the original Provider. It would 

be sufficient for each Principal User or 

End User transferring the materials to 

verify the legitimacy of the recipient 

during each transfer and for all parties 

to retain a record of it for at least three 

years, and longer (e.g., eight years) if 

this does not pose an undue burden on 

their operations. 

Providers should be aware of 

regulatory and statutory prohibitions 

related to U.S. persons dealing with 

certain foreign persons, entities, and 

companies. Providers are encouraged to 

check the Customer against the 

International Trade Administration 

consolidated list of individuals and 

entities for which the U.S. government 

maintains restrictions on certain 

exports, re-exports, or transfers of 


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Federal Register / Vol. 88, No. 197 / Friday, October 13, 2023 / Notices 71003 

16https://www.trade.gov/consolidated-screeninglist. 

items.16 In the event that a company, 

entity, or person on the list appears to 

match that of a customer or other 

recipient, additional due diligence 

should be conducted before proceeding. 

There may be a strict export prohibition, 

a requirement for seeking a license 

application, or other evaluation of the 

Customer or other recipient necessary to 

ensure it does not result in an activity 

prohibited by any U.S. export 

regulations, or other restrictions. Before 

fulfilling the order, to ensure full 

compliance with all the terms and 

conditions of the restrictions placed on 

the parties on this list, the Provider 

must check the official publication of 

restricted parties in the Federal 

Register. 

VII. Following Up With the U.S. 

Government in Cases Where Malintent 

is Suspected by Providers, Third-Party 

Vendors, or Manufacturers 

If sequence or Customer screening 

raises concerns that are not alleviated 

through follow-up screening, Providers, 

Third-Party Vendors, and Manufacturers 

should not fulfill the order and are 

strongly encouraged to contact their 

nearest FBI Field Office’s WMD 

Coordinator. Institutions are encouraged 

to work with their Principal Users and 

End Users to help them understand that 

only individuals with legitimate, bona 

fide, and peaceful purpose should 

obtain synthetic nucleic acids 

containing SOCs. 

VIII. Records Retention 

The Guidance recommends that 

Providers, Third-Party Vendors, and 

Manufacturers retain the following 

types of records for at least three years, 

and longer (e.g., eight years) if this does 

not pose an undue burden on their 

operations: 

• Records of Customer orders 

including the following information: 

Customer information (point-of contact 

name, organization, address, email, and 

phone number), order sequence 

information (nucleotide sequences 

ordered, vector used), and order 

information (date placed and shipped, 

shipping address, receiver name); 

• Records of protocols for sequence 

screening and for determining whether 

a sequence hit qualifies as a SOC; 

• Records of screening 

documentation of all hits, even if the 

order was deemed acceptable; 

• Records of any follow-up screening, 

even if the order was ultimately filled; 

and 

• The ultimate disposition of any 

SOC orders, with documentation of 

reasoning for final decision (fulfill 

versus deny). 

IX. Periodic Review, Evaluation, and 

Improvement of This Guidance 

This Guidance addresses biosecurity 

risks that have emerged in a dynamic 

and rapidly developing technological 

landscape. It is likely that new risks will 

emerge and that new technological 

approaches will also appear to address 

them. As such, this Guidance 

encourages the further development of 

mechanisms to detect SOCs and 

screening strategies for sequences that 

contribute directly to pathogenicity and 

toxicity. For instance, strategies may be 

used by malicious Customers to 

obfuscate SOCs, including engineering 

pathogenic or toxic proteins with 

completely novel sequences. In such 

cases, synthetic nucleic acid orders may 

contain 50 nt windows that are not a 

match to any known sequence. 

Although there are likely legitimate 

explanations for orders of sequences 

with no matches in existing databases 

(e.g., nucleic acids ordered to populate 

microarrays or to store digital 

information), in such cases, it may be 

possible to use predictive bioinformatic 

algorithms to screen sequences that are 

not a match to any known sequences to 

determine if they could produce 

proteins that are structurally and 

functionally identical to SOCs. This 

Guidance encourages Providers to 

continue to develop these methods to 

best ensure the safety and security of the 

synthetic nucleic acid research 

enterprise. 

This Guidance will be periodically 

revisited, including by soliciting 

stakeholder input, and feedback is 

encouraged from the nucleic acid 

synthesis industry as well as from their 

customers as they implement the 

Guidance. Furthermore, implementation 

of this Guidance will be supported 

through the publication of a Companion 

Guide. 

Dawn O’Connell, 

Assistant Secretary for Preparedness and 

Response. 

[FR Doc. 2023–22540 Filed 10–12–23; 8:45 am] 

BILLING CODE 4150–37–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Biomedical Advanced Research and 

Development Authority Industry Day 

2023 

AGENCY: Administration for Strategic 

Preparedness and Response (ASPR), 

Department of Health and Human 

Services (HHS). 

ACTION: Notice. 

SUMMARY: The Biomedical Advanced 

Research and Development Authority 

(BARDA) annually hosts BARDA 

Industry Day (BID), a two-day 

conference with industry and our 

government partners to share BARDA’s 

goals and objectives, increase awareness 

of U.S. government medical 

countermeasure (MCM) priorities, and 

facilitate collaboration between public 

and private sectors within the health 

security space. This year, BARDA plans 

to discuss implementation efforts for 

our 2022–2026 Strategic Plan, which 

focuses on strengthening the health 

security of the nation, embracing 

lessons learned from the COVID–19 

pandemic, incorporating new avenues 

of promising research and development, 

and addressing the imperative for 

MCMs that are safe, effective, and 

widely accessible. 

DATES: BID 2023 will be a hybrid event, 

held from Monday, November 13– 

Tuesday, November 14, 2023. The 

meeting will begin each day at 9 a.m. 

Eastern Standard Time. 

ADDRESSES: This meeting is open to the 

public. Register here: https://

medicalcountermeasures.gov/barda/ 

barda-industry-day-2023/. 

FOR FURTHER INFORMATION CONTACT: 

Ezinne N. Ebi, Biomedical Advanced 

Research & Development Authority 

(BARDA), ezinne.ebi@hhs.gov, (202) 

989–5539. 

Dawn O’Connell, 

Assistant Secretary for Preparedness and 

Response. 

[FR Doc. 2023–22539 Filed 10–12–23; 8:45 am] 

BILLING CODE 4150–37–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

National Institutes of Health 

National Institute of Biomedical 

Imaging and Bioengineering; Notice of 

Meeting 

Pursuant to section 1009 of the 

Federal Advisory Committee Act, as 

amended, notice is hereby given of a 

meeting of the National Advisory 

Council for Biomedical Imaging and 

Bioengineering. 

The meeting will be open to the 

public by videocast as indicated below. 

Individuals who plan to attend and 

need special assistance, such as sign 

language interpretation or other 

reasonable accommodations, should 


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