Frequently Asked Questions

As in the original Guidance, a primary goal is to minimize the risk that unauthorized individuals or individuals with malicious intent will use nucleic acid synthesis technologies to obtain organisms for which possession, use, and transfer is regulated by Federal Select Agent Program (FSAP) and Commerce Control List (CCL). The Revised Guidance also aims to limit the potential for individuals to use synthetic oligonucleotides to create novel dangerous pathogens using sequences from unregulated organisms. The chemical synthesis of oligonucleotides potentially allows for the generation and modification of some viruses and bacteria. More specifically, oligonucleotide synthesis could enable individuals to synthesize pathogens for which they do not have a legitimate need or to increase the pathogenicity or toxicity of agents that they are able to access, through the use of modern molecular biological methods. Also, as these methods have made the conversion of different types of oligonucleotides increasingly easy, it is necessary to expand this Revised Guidance to include both single and double-stranded form of both RNA and DNA. The proposed Revised Guidance also suggests that order batch size should be considered in the sequence screening, to identify orders of small oligonucleotides that could be assembled into larger sequences of concern.

The proposed Revised Guidance is a draft submitted for public review and comment for 60 days. Stakeholder comments will be considered by an interagency working group (IWG), led by the Office of the Assistant Secretary for Preparedness and Response. The IWG will develop a Final Revised Guidance and issue it for publication in the Federal Register in late 2022 or early 2023.

Publication of the Final Revised Guidance will not establish new regulations. Adherence is voluntary, as no federal laws require compliance with this Guidance, and no HHS or other federal agency currently requires compliance with the Guidance as a condition for research funding. The proposed Revised Guidance provides recommendations on baseline standards for providers of synthetic oligonucleotides, customers and users of these products, and for manufacturers of benchtop oligonucleotide synthesizers. These recommendations are intended to enhance communication between providers and customers to streamline the sequence and customer screening processes, to ensure that all entities are aware of best practices they should adopt to mitigate the risks associated with oligonucleotides encoding sequences of concern, encourage the responsible screening of customers and users, and to encourage the establishment of best practices in the manufacturing of benchtop oligonucleotide synthesis equipment. Some specific recommendations serve to remind entities of their obligations under existing regulations, but no new regulations are imposed.

The U.S. government, the synthetic biology industry, and the scientific community recognize that there are concerns that synthetic oligonucleotide sequences not unique to select agents or toxins or Commerce Control List items also pose a biosecurity concern. The open availability of genetic sequence data poses concerns, that individuals with ill intent could exploit biotechnology for harmful purposes. The U.S. government has acted to reduce dangers to human, animal, and plant health due to biological pathogens and toxins on the select agents and toxins list and Commerce Control List. However, these regulated pathogens and toxins do not represent the entirety of the potential risks to public health, agriculture, plants, animals, or the environment that could arise from the misuse of synthetic oligonucleotides. Non-regulated pathogens and toxins as well as other novel types of sequences or specific types of batch orders, may also pose significant risks if they are misused. The proposed Revised Guidance seeks to more fully encompass the risks associated with synthetic oligonucleotides by including all sequences that contribute to pathogenicity or toxicity in the definition of sequences of concern.

While developing Screening Framework Guidance for Providers and Users of Synthetic Oligonucleotides, the Interagency Working Group consulted with representatives of synthetic oligonucleotides providers to understand their current practices. While there may be some differences in screening methodology details between the U.S. government approach and individual providers, as well as differences among providers, the overarching recommendations and intent are consistent among best practices in the industry. The proposed screening approach strikes a balance between mitigating biosecurity risks and minimizing any negative impacts on the conduct of research or business operations. Specifically, guidance encourages customers to pre-emptively identify that their orders contain sequences of concern (if known) and provide information that verifies their legitimacy.

Open communication between Customers and Providers will facilitate the screening process and validate orders that contain sequences of concern (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 pre-emptively demonstrate legitimacy. Providers can facilitate this information sharing by including a mechanism for such self-reporting and verification in their ordering process.

Individuals with no legitimate, bona fide, and peaceful need should be prevented from accessing genetic materials that could contribute to pathogenicity or harm, even when they are not from Federal Select Agent Program (FSAP)- or CCL-listed pathogens or toxins. Information that would allow Providers, Manufacturers, Principal Users, or End Users to authenticate the recipient of materials or equipment as a legitimate member of the scientific community is critical to ensuring that sequences of concern are handled responsibly. Information such as proposed end-use of the order, institutional or corporate affiliation (if applicable), the name of a biosafety officer (if available), proof of registration or licensing with FSAP or Department of Commerce (if applicable), or other proof of a legitimate research program (such as a publication history or business licenses) may be helpful for such verification.

The proposed Revised Guidance recommends recording transfers of oligonucleotides containing sequences of concern (SOCs) from Principal Users and End Users to any other individuals not listed in the original order, such as through a Material Transfer Agreement (MTA) or another sample tracking process. The proposed Revised Guidance also recommends that records of SOCs and their transfers are retained for at least 8 years. Business practices already in place at Institutions may be used to fulfill this recommendation.

The proposed Revised Guidance aims to ensure that Customers, Principal Users, and End Users ordering sequences of concern (SOCs) are legitimate. It also recommends that Manufacturers install certain safeguards in oligonucleotide synthesis equipment that ensure only legitimate customers can synthesize SOCs. It also recommends that transfers of SOCs, from Principal Users to End Users, and from Third-Party Vendors to Principal Users and End Users, are reported to the original Customer, such as the Institution that originated the order. This proposed Revised Guidance encourages entities transferring synthetic oligonucleotides containing SOCs (i.e., the Third-Party Vendor, Principal User, or Institution) to know to whom they are transferring and to conduct suitability screening to verify that the recipients have a legitimate, bona fide, and peaceful purpose to use the oligonucleotides. The proposed Revised Guidance recommends that the Customers who place these orders use responsible business practices to maintain records of transfers.

Manufacturers of benchtop synthesis equipment are encouraged to consider three areas for developing best practices in this context: customer screening to ensure that the user has a legitimate purpose for obtaining oligonucleotide synthesis equipment; implementing mechanisms to track continuously the legitimacy of users of their equipment, including when it is potentially transferred to new Principal and End Users during the lifecycle of these equipment; and, providing the capability into their oligonucleotide synthesizers to enable secure internet connectivity to screen sequences for sequences of concern and to authenticate legitimate users. Manufacturers are also encouraged to include a data logging function to maintain a record of the oligos synthesized on the equipment.