[Federal Register Volume 74, Number 227 (Friday, November 27, 2009)]
[Notices]
[Pages 62319-62327]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E9-28328]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Office of the Secretary
Screening Framework Guidance for Synthetic Double-Stranded DNA
Providers
AGENCY: Department of Health and Human Services, Office of the
Secretary.
ACTION: Notice.
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Authority: Public Health Service Act, 42 U.S.C. 241, Section
301; HSPD-10.
SUMMARY: To reduce the risk that individuals with ill intent may
exploit the commercial application of nucleic acid synthesis technology
to access genetic material derived from or encoding Select Agents or
Toxins, the U.S. Government has developed recommendations for a
framework for synthetic nucleic acid screening. This document is
intended to provide guidance to producers of synthetic genomic products
regarding the screening of orders so that these orders are filled in
compliance with current U.S. regulations and to encourage best
practices in addressing potential biosecurity concerns. Following this
guidance is voluntary, though many specific recommendations serve to
remind providers of their obligations under existing regulations. The
target audience for this guidance is the gene and genome synthesis
industry, because the technical hurdles for de novo synthesis of Select
Agents and Toxins from double-stranded DNA are much lower than for de
novo synthesis of these agents from single-stranded oligonucleotides.
This guidance proposes a screening framework for commercial providers
of synthetic double-stranded DNA 200 base pairs (bps) or greater in
length to address concerns associated with the potential for misuse of
their products. The framework includes customer screening and sequence
screening, follow-up screening as necessary, and consultation with U.S.
Government contacts, as needed.
This guidance is submitted for public consideration and comment for
a period of 60 days. The Office of the Assistant Secretary of
Preparedness and Response (ASPR) within the Department of Health and
Human Services (HHS) is submitting this document for public
consideration as the lead agency in a broad interagency process to
draft the guidance.
DATES: The public is encouraged to submit written comments on this
proposed action. Comments may be submitted to HHS/ASPR in electronic or
paper form at the HHS/ASPR e-mail address, mailing address, and fax
number shown below under the heading FOR FURTHER INFORMATION CONTACT.
All comments should be submitted by January 26, 2010. All written
comments received in response to this notice will be available for
review by request.
FOR FURTHER INFORMATION CONTACT: Jessica Tucker, Ph.D., Office of
Medicine, Science, and Public Health, Office of the Assistant Secretary
for Preparedness and Response, U.S. Department of Health and Human
Services, 330 C Street, SW., Room 5008B, Washington, DC 20201; phone:
202-260-0632; fax: 202-205-8494; e-mail address:
[email protected].
SUPPLEMENTARY INFORMATION:
Screening Framework Guidance for Synthetic Double-Stranded DNA
Providers
I. Summary
Synthetic biology, the developing interdisciplinary field that
focuses on both the design and fabrication of novel biological
components and systems as well as the re-design and fabrication of
existing biological systems, is poised to become the next significant
transforming technology for the life sciences and beyond. Synthetic
biology is not constrained by the requirement of using existing genetic
material. Thus, technologies that permit the directed synthesis of
polynucleotides have great potential to be used to generate organisms,
both currently existing and novel, including pathogens that could
threaten public health, agriculture, plants, animals, the environment,
or material. To reduce the risk that individuals with ill intent may
exploit the commercial application of nucleic acid synthesis technology
to access genetic material derived from or encoding Select Agents or
Toxins, the U.S. Government has developed recommendations for a
framework for synthetic nucleic acid screening. This document is
intended to provide guidance to producers of synthetic genomic products
regarding the screening of orders so that these orders are filled in
compliance with current U.S. regulations and to encourage best
practices in addressing potential biosecurity concerns.
Following this guidance is voluntary, though many specific
recommendations serve to remind providers of their obligations under
existing regulations. The target audience for this guidance is the gene
and genome synthesis industry, because the technical hurdles for de
novo synthesis of Select Agents and Toxins from double-stranded DNA are
much lower than for de novo synthesis of these agents from single-
stranded oligonucleotides. This guidance proposes a screening framework
for commercial providers of synthetic double-stranded DNA 200 base
pairs (bps) or greater in length to address concerns associated with
the potential for misuse of their products. The framework includes
customer screening and sequence screening, follow-up screening as
necessary, and consultation with U.S. Government contacts, as
[[Page 62320]]
needed. Briefly, upon receiving an order for synthetic double-stranded
DNA, the U.S. Government recommends that the provider perform customer
screening. If the information provided by the customer raises any `red
flags,' providers should perform follow-up screening. If no customer
identity concerns or other `red flags' are raised in customer
screening, sequence screening is recommended. If sequence screening
raises any concerns, providers should pursue follow-up screening to
clarify the end-use of the ordered sequence. If follow-up screening
does not resolve concerns about the order or there is reason to believe
a customer may intentionally or inadvertently violate U.S. laws,
providers should contact designated entities within the U.S. Government
for further information. This guidance also provides recommendations
regarding proper records retention protocols and screening software.
II. Introduction
Synthetic biology is distinct from traditional recombinant DNA
technology in some key aspects: (1) It is not constrained by the
requirement for using existing genetic material, and (2) it is an
interdisciplinary field that includes biologists, engineers, chemists,
and computer modelers. It is the former novel feature, along with rapid
advances in DNA synthesis technology and the open availability of
pathogen genome sequence data, that has raised concerns in the
scientific community, the nucleic acid synthesis industry, the U.S.
Government, and the general public.
Within the U.S., microbial organisms and toxins that have been
determined to have the potential to pose a severe threat to public
health and safety, animal health, plant health, or animal or plant
products are regulated through the Select Agent Regulations (SAR),
administered by the Department of Health and Human Services/Centers for
Disease Control and Prevention (CDC) and the U.S. Department of
Agriculture/Animal and Plant Health Inspection Service (USDA/APHIS).
The SAR sets forth requirements for the possession, use, and transfer
of listed agents. Technologies that permit the directed synthesis of
polynucleotides, which underlie synthetic biology and more specifically
synthetic genomics, could enable individuals not authorized to possess
Select Agents to gain access to them through their de novo synthesis.
Such synthesis obviates the need for access to the naturally occurring
agents or naturally occurring genetic material from these agents,
thereby greatly expanding the potential availability of these agents.
The National Science Advisory Board for Biosecurity (NSABB) was
charged with identifying the potential biosecurity concerns raised by
the ability to synthesize Select Agents and providing advice on whether
current U.S. Government policies and regulations adequately cover the
de novo synthesis of Select Agents. Their report entitled Addressing
Biosecurity Concerns Related to the Synthesis of Select Agents was
formally transmitted to the U.S. Government in March 2007. Federal
Departments and Agencies with equities relevant to life science
research and/or security deliberated over the NSABB recommendations and
identified a series of relevant policy actions targeted to promote risk
management, while seeking to minimize negative impacts upon scientific
progress or industrial development.
One of the formal policy actions in regard to Synthetic DNA and
Biological Security charged Federal Departments and Agencies to
``engage stakeholders in industry and academia to identify, evaluate
and support the establishment of a screening infrastructure for use by
commercial providers and users of synthetic nucleic acids.'' Toward
this end, this document provides guidance to synthetic nucleic acid
providers regarding a screening framework for synthetically derived
double-stranded DNA orders that are 200 bps or greater in length.
Specific recommendations are in bold type throughout the text.
III. Goals of Guidance
The primary goal in developing guidance for synthetic nucleic acid
providers is to minimize the risk that unauthorized individuals or
individuals with malicious intent will gain access to toxins and
organisms of concern through the use of nucleic acid synthesis
technologies, while at the same time minimizing any negative impacts on
the conduct of research and business operations. These guidelines were
developed to be easily integrated within providers' existing protocols
with minimal cost, and to be globally extensible, both for U.S.-based
firms operating abroad and for international companies.
Providers of synthetic nucleic acids have two overriding
responsibilities in this context:
Providers should know to whom they are selling a product
Providers should know if the nature and identity of the
product that they are selling poses a hazard to public health,
agriculture, or security
To help providers meet these responsibilities, this guidance
outlines a screening framework that addresses both customer screening
(customer identity) and sequence screening (product identity). Though
certain guidance provided in this document is necessarily framed by
U.S. policy and regulations, the guidelines were composed so that
fundamental goals, provider responsibilities, and the screening
framework could be considered for application by the international
community. In particular, though the Select Agents and Toxins that are
a primary focus of these guidelines may not be relevant for all
countries, the sequence screening framework has been developed so that
it could be applied to other categories of agents that may be relevant
for other regions.
IV. Overall Process: Synthetic Nucleic Acid Screening Framework
Providers should consider establishing a comprehensive and
integrated screening framework that includes both customer screening
and sequence screening.
Customer Screening--The purpose of customer screening is
to establish the legitimacy of customers ordering synthetic nucleic
acid sequences, both at the level of the individual and the
organization. Providers should develop customer screening mechanisms to
verify customer identities, to identify potential `red flags,' and to
conform to U.S. trade restrictions and export control regulations.
Sequence Screening--The purpose of sequence screening is
to identify when sequences of concern are ordered. Identification of a
sequence of concern does not necessarily imply that the order itself is
of concern. Rather, when a sequence of concern is ordered, further
customer screening procedures should be used to determine if filling
the order would raise cause for concern. Sequence screening is
currently being recommended for all double-stranded DNA 200 bps or
greater in length.
Many customers will likely volunteer information about their
identity or the sequence they are ordering. Providers should
corroborate this information as part of their screening framework.
The following overall screening methodology is recommended:
1. Upon receiving an order for synthetic double-stranded DNA, the
U.S. Government recommends reviewing the information provided by the
customer to verify their identity and identify potential `red flags'
(referred to as customer screening). If the information provided raises
any
[[Page 62321]]
concerns, providers should ask the customer for additional information
to clarify the customer's need for the order and its intended end-use
(referred to as follow-up screening). Providers should also check
customers and their affiliated organizations against lists of denied or
blocked persons and entities maintained by the Departments of Commerce,
State, and Treasury.
2. If no concerns or `red flags' are raised during customer
screening, the U.S. Government recommends screening the ordered
sequence to identify sequences derived from or encoding Select Agents
and Toxins \1\ (referred to as sequence screening). For international
customers, providers should also screen the ordered sequence to
identify sequences derived from or encoding the agents and toxins on
the Export Administration Regulation's (EAR's) Commerce Control List
(CCL).\2\ Scenarios of concern may include:
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\1\ Please see http://www.selectagents.gov to access the most
recent Select Agents and Toxins List.
\2\ Visit http://www.access.gpo.gov/bis/ear/ear_data.html to
access the most recent Commerce Control List and review the Export
Administration Regulations.
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a. If an ordered nucleic acid can be classified as a Select Agent
or Toxin based on the SAR \3\ or is identified as a sequence of concern
(defined in Section V.B.1.), additional customer verification steps
should be performed and may in some cases be required.
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\3\ The CDC/APHIS national Select Agent registry Web site
(http://www.selectagents.gov) contains a guidance document entitled
``Applicability of the Select Agent Regulations to Issues of
Synthetic Genomics'' to assist providers in identifying
synthetically derived Select Agent materials that would fall under
the current regulations. The regulation of Select Agents and Toxins
currently includes (1) Nucleic acids that can produce infectious
forms of any Select Agent viruses and (2) Recombinant nucleic acids
that encode for the functional form(s) of any of the regulated
toxins if the nucleic acids: (i) Can be expressed in vivo or in
vitro, or (ii) Are in a vector or recombinant host genome and can be
expressed in vivo or in vitro.
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b. If an ordered nucleic acid can be classified as a Select Agent
or Toxin based on the SAR, providers must be registered under the SAR
to possess the nucleic acid. Transfer of the material from the producer
must be done in accordance with USDA APHIS and CDC procedures using the
APHIS/CDC Form 2 to obtain authorization for and to document the
transfer. Additional information on the transfer of select agents and
toxins is available at http://www.selectagents.gov.
c. If an order is defined as a genetic element that is listed on
the CCL, additional restrictions or licensing requirements may exist
for international orders.
3. If sequence screening or customer screening raises any concerns,
providers should pursue follow-up screening to clarify the end-use of
the ordered sequence. The goal of follow-up screening is to assist the
provider in determining whether to fill the order. If the provider
encounters a scenario where they would benefit from additional
assistance in assessing an order, the provider is encouraged to seek
advice from the relevant U.S. Government Departments and Agencies by
contacting the nearest FBI Field Office Weapons of Mass Destruction
(WMD) Coordinator. The WMD Coordinator can be reached by contacting the
local FBI Field Office and asking to be connected to the FBI WMD
Coordinator.
V. Pertinent Screening Definitions and Details
This section reviews pertinent definitions and provides details of
the steps involved in the recommended screening framework. These steps
include customer screening, sequence screening, and follow-up
screening.
A. Customer Screening
Customer screening encompasses two overarching responsibilities of
providers: Customer verification and identification of any `red flags.'
1. Customer Verification
To ensure compliance with U.S. regulations concerning exports and
sanctioned individuals and countries, the U.S. Government recommends
that, for every order, synthetic nucleic acid providers:
(1) Gather the following information to verify a customer's
identity:
Customer's (and end-user's, if different) full name and
contact information
Billing address and shipping address (if not the same)
Customer's institutional or corporate affiliation (if
applicable)
Name of institution's Biological Safety Officer (if
applicable)
(2) Screen customers against several lists of proscribed entities
(described in Section VI).
Lack of affiliation with an institution or firm does not
automatically indicate that a customer's order should be denied. In
such cases, the U.S. Government recommends conducting follow-up
screening.
The U.S. Government recommends that companies retain electronic
copies of customer orders for at least eight years based on the statute
of limitations set forth by U.S. Code Title 18 Section 3286.\4\
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\4\ The eight-year statute of limitations in Section 3286
applies to the offense defined by Title 18 Section 175(b)
(possession of biological agents with no reasonable justification).
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The U.S. Government recommends archiving the following information:
Customer (and end-user, if different) information (name, organization,
address, and phone number), order sequence information, and order
information (date placed and shipped, shipping address, and receiver
name).
2. `Red Flags'
In reviewing the customer's order information, providers should
take into account any circumstances in the proposed transaction that
may indicate that the order may be intended for an inappropriate end-
use, end-user or destination. These are known as `red flags.'
The following is an illustrative list of indicators that can help
in identifying suspicious orders of synthetic double-stranded DNA:
A customer whose identity is not clear, who appears
evasive about their identity or affiliations, or whose information
cannot be confirmed or verified (e.g., addresses do not match, not a
legitimate company, no Web site, cannot be located in trade
directories, etc.).
A customer or intermediary agent who would not be expected
in the course of their normal business to place such an order (e.g., no
connection to life science research, biotechnology or requirement for
DNA synthesis services).
An unusually large order of DNA sequences, including
larger than normal quantities, the same order placed several times, or
several orders of the same sequence made in a short timeframe.
A customer that requests unusual labeling or shipping
procedures (e.g., requests to misidentify the goods on the packaging,
requests to deliver to a private address, or requests to change the
customer's name after the order is placed, but before it is shipped).
A customer proposing an unusual method of payment (e.g.,
arranging payment in cash, personal credit card or through a non-bank
third party) or offering to pay unusually favorable payment terms, such
as a willingness to pay a higher than expected price.
A customer that requests unusual confidentiality
conditions regarding the order, particularly with respect to the final
destination or the destruction of transaction records.
[[Page 62322]]
If a review of customer information reveals one or more `red
flags,' the U.S. Government recommends that providers exercise due
diligence, inquire regarding the circumstances, and verify the end-use
and end-user (see follow-up screening). If providers are unsure about
whether to fill an order, they should contact the U.S. Government for
further information.
B. Sequence Screening
Sequence screening is intended to elicit information detailing the
characteristics of the ordered nucleic acid sequence and to determine
whether the customer has placed an order for a sequence of concern,
based on the product identity. Providers should screen ordered
sequences that are 200 bps in length or greater.
1. Identifying Sequences of Concern
The U.S. Government recommends that nucleic acid sequences be
screened for nucleic acids derived from or encoding Select Agents and
Toxins and, for foreign orders, for nucleic acids derived from or
encoding pathogens and toxins on the Commerce Control List. The U.S.
Government chose the agents and toxins identified by HHS and USDA as
``Select Agents and Toxins'' as the most appropriate list of agents of
concern against which providers should screen orders since:
The list is comprised of high consequence pathogens and
toxins that have the potential to pose a severe threat to human,
animal, or plant health or to animal or plant products
Their possession, use, and transfer are managed through
Federal regulations.
A list of biological agents and toxins that affect humans has been
promulgated by HHS/CDC (HHS Select Agents and Toxins, 42 CFR 73.3). A
list of biological agents that affect animals and animal products has
been promulgated by USDA/APHIS/Veterinary Services (USDA Select Agents
and Toxins, 9 CFR 121.3). A list of agents that affect plants and plant
products has been promulgated by USDA/APHIS/Plant Protection and
Quarantine (USDA Select Agents and Toxins, 7 CFR 331.3). Additionally,
HHS and USDA promulgated a list of ``overlap'' agents that affect both
humans and animals (42 CFR 73.4 and 9 CFR 121.4). The Select Agent and
Toxins lists are reviewed biennially and updated as needed to include
additional agents or toxins that may pose a biosecurity concern.
Therefore, for the purposes of this guidance, ``agents of concern'' are
classified as Select Agents and Toxins, and ``sequences of concern''
are sequences derived from or encoding Select Agents and Toxins. For
foreign orders, ``agents of concern'' also include pathogens and toxins
on the EAR's CCL, and ``sequences of concerns'' includes those nucleic
acids derived from or encoding those pathogens and toxins.\5\
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\5\ The EAR provisions are subject to change, as they are
regularly updated pursuant to multilateral agreements.
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If a customer orders a synthetic nucleic acid that can be
classified as a Select Agent or Toxin, the provider must abide by the
CDC and USDA/APHIS Select Agent Regulations (42 CFR 73, 7 CFR 331, and
9 CFR 121). The CDC/APHIS national Select Agent registry Web site
(http://www.selectagents.gov) contains a guidance document developed by
the national Select Agent regulatory programs to assist providers in
identifying synthetically derived Select Agent materials that would
fall under the current regulations. Providers of regulated nucleic
acids must be registered with CDC or APHIS in order to synthesize these
materials.
The U.S. Government acknowledges that there are synthetic nucleic
acid sequences from non-Select Agents or Toxins that may pose a
biosecurity concern. Synthetic nucleic acid providers may choose to
investigate such sequences as part of their best practices. However,
due to the complexity of determining pathogenicity and because research
in this area is ongoing, a list of additional non-Select Agent or Toxin
sequences or organisms to screen against would not be comprehensive and
consequently are not provided by the U.S. Government in this guidance.
Because the CCL and the Select Agents and Toxins list are not
identical, separate screening for those sequences on the CCL is
recommended for international orders.
2. Technical Goals and Recommendations for Sequence Screening
The reliable and accurate detection of synthetic nucleic acid
sequences derived from or encoding sequences or agents of concern is
the primary goal of sequence screening. In considering various sequence
screening methodologies, the U.S. Government developed the following
list of specific technical goals and recommendations for a sequence
screening methodology:
The U.S. Government recommends that the sequence screening method
should identify sequences unique to Select Agents and Toxins. Many DNA
sequences encode genes that are required to maintain normal cellular
physiology, otherwise known as ``house-keeping genes.'' These ``house-
keeping genes'' are highly conserved between pathogenic and non-
pathogenic species. Screening methodologies that recognize highly
conserved sequences such as ``house-keeping genes'' as positive hits
for sequences of concern not only offer little to no biosecurity
benefit, but may impede the screening efforts. Such methodologies would
produce a larger number of hits adding extra burden for screeners and
potentially resulting in actual sequences of concern being overlooked.
Additionally, such a system may hamper scientific research by falsely
assigning sequences from closely related microbes as sequences of
concern.
The U.S. Government recommends that sequence screening be performed
for both DNA strands and the resultant polypeptides derived from
translations using the three alternative reading frames on each DNA
strand (or six-frame translation). Each amino acid is encoded by a
codon, a three nucleotide sequence of DNA. The correspondence from
codon to amino acid is not unique. A given amino acid may be encoded by
one to six distinct codons, which means that an amino acid polypeptide
can be encoded by many different DNA sequences. Consequently, to
determine whether a nucleotide sequence encodes for a sequence or agent
of concern, it is necessary to screen the six-frame translation
polypeptides encoded by the DNA sequences in addition to the DNA
sequences themselves.
The U.S. Government recommends that sequence alignment methods
should permit the detection of ``sequences of concern'' of 200 bps that
may be hidden within larger sequence orders. Genes vary widely in
length. If a sequence screening system assesses only the overall
sequence length without any local checks, a sequence of concern can go
undetected if inserted within a larger, benign sequence. The screening
routine should be capable of local sequence alignments to ensure that
potentially harmful sequences, embedded within larger sequences, are
not overlooked. 200 bps is set as the limit for sequences of concern
since synthetic nucleic acids smaller than 200 bps can be readily
ordered as oligonucleotides, and gene synthesis companies are the
target audience for this guidance.
3. Sequence Screening Methodology
The U.S. Government considered two distinct screening approaches,
one based on a curated database of known sequences of concern and
another utilizing a method called ``Best Match.''
[[Page 62323]]
The first approach requires the creation of databases identifying
specific features such as known pathogenic sequences, virulence
factors, house-keeping genes, etc. While the acquisition of such
knowledge is progressing, at this time customized database approaches
are unable to provide a robust solution that can be implemented by DNA
synthesis providers.
Consequently, the U.S. Government recommends a ``Best Match''
approach for sequence screening. In this approach, a query sequence is
deemed to be unique to a Select Agent or Toxin if the sequence (amino
acid) is more closely related to a Select Agent or Toxin sequence than
to a non-Select Agent or Toxin sequence. Sequences that are equally
related to both a Select Agent or Toxin and a non-Select Agent or Toxin
will not produce a sequence hit. As a result, the number of hits for
sequences that can be obtained from non-Select Agents and Toxins will
be reduced. To meet the goals and recommendations stated above, the
U.S. Government recommends that each sequence be broken into a six-
frame translation of 200 bp nucleotide segments. Each resulting 66
amino acid sequence should be compared to the GenBank protein sequence
database using a sequence alignment tool. The ``Best Match'' is the
sequence or sequences with the greatest percent identity over the
entire 66 amino acid sequence. If the ``Best Match'' is to a Select
Agent or Toxin sequence, with no equivalent hits to a non-Select Agent
or Toxin, the order should be further investigated by the provider as a
potential sequence hit.
The ``Best Match'' approach is intended to minimize the number of
sequence hits due to genes that are shared among both Select Agents or
Toxins and non-Select Agents or Toxins. Nonetheless, some harmless
sequences in Select Agents or Toxins or those that are routinely used
in scientific research may result in a hit during this sequence screen.
The U.S. Government recommends that providers develop, maintain,
and document protocols to determine if a sequence hit qualifies as a
true sequence of concern. Additionally, providers should keep records
of all hits even if the order is deemed acceptable. In cases where the
provider is unable to make the determination, advice can be sought from
the relevant U.S. Government Departments and Agencies by contacting the
nearest FBI Field Office Weapons of Mass Destruction Coordinator.
The provider may deem some sequences from non-Select Agents and
Toxins to be a biosecurity concern. The U.S. Government recommends that
providers continue to exercise their due diligence in the investigation
of screening hits against non-Select Agents and Toxins that may raise a
biosecurity concern.
These sequence screening methodology recommendations do not
preclude the use of curated databases in addition to the ``Best Match''
approach. The development of such databases is encouraged as an
additional screening tool that will improve with time as additional
data becomes available. Providers may choose to use other screening
approaches that they assess to be equivalent or superior to the ``Best
Match'' approach. The U.S. Government recommends that providers
develop, maintain, and document their sequence screening protocol
within company records.
The U.S. Government recognizes that continued research and
development may lead to new and improved screening methodologies. As
new methods are developed, U.S. guidance may change accordingly.
C. Follow-Up Screening
Follow-up screening may be warranted if customer screening reveals
any `red flags' or sequence screening results in a hit. In any case
where there are abnormal circumstances surrounding the order or the
customer has ordered a sequence of concern, the U.S. Government
recommends that providers ask for information regarding the customer's
proposed end-use of the order to help assess their need and the
scientific legitimacy of their work. Sample end-uses of ordered
synthetic nucleic acids could include, but are not limited to:
Identification of pathogenicity genes via marker-deletion
mutagenesis
Training for threat agent detection
Production of organism for experimental research studies
If the customer is associated with an institution or firm,
providers should also contact the customer's biological safety officer,
supervisor, lab director or director of research in order to verify the
customer's identity and need. If the customer is not affiliated with an
institution or firm, providers should also conduct a literature review
of the customer's past research to verify his or her identity and need.
VI. Recommended Processes for Domestic and International Orders
This section outlines recommendations for specific screening
processes for orders from domestic and international customers. The
customer screening, sequence screening, and follow-up screening
protocols that are referenced in this section are defined and described
in Section V. Most of the information provided in this section serves
as a reminder to providers to ensure they are meeting their legal
obligations not to conduct unapproved business transactions with
certain proscribed entities.
A. Domestic Orders
Once a domestic customer order is received, the provider should
conduct customer screening.
In addition to verifying the customer identity and identifying any
`red flags,' providers should be aware of regulatory and statutory
prohibitions for U.S. persons from dealing with certain foreign
persons, entities and companies. In order to avoid violating U.S. law,
providers are encouraged to check the individual placing the order and
the individual's affiliated institution (when applicable) against
several lists of proscribed entities before filling each order,
including the:
Department of Treasury Office of Foreign Assets Control
(OFAC) list of Specially Designated Nationals and Blocked Persons (SDN
List).
Department of State list of persons engaged in
proliferation activities.
Department of Commerce Denied Persons List (DPL).
According to U.S. regulations, no U.S. persons or entities may
conduct business transactions with individuals or entities on the SDN
List without a license from OFAC. This list is maintained by OFAC. OFAC
only provides a license to deal with individuals on the SDN List in
extremely limited circumstances.\6\
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\6\ Additional information, including the SDN List, is available
at: http://www.treas.gov/offices/enforcement/ofac/sdn/.
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According to U.S. regulations, no U.S. persons or entities may
conduct business transactions with individuals sanctioned by the
Department of State for engaging in proliferation activities.\7\
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\7\ Announcements of such sanctions determinations are printed
in the Federal Register and are maintained on the Department of
State's Web site (http://www.state.gov/t/isn/c15231.htm).
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Additionally, the U.S. Government recommends that providers screen
customers against the DPL for domestic orders. This list includes those
firms and individuals whose export privileges have been denied. While
the Department of Commerce only regulates exports and therefore does
not require that companies screen their domestic customers against the
list, it recommends that they do so, to avoid
[[Page 62324]]
unwittingly passing on sensitive technology or materials to U.S.
residents known to be involved in proliferation activities.\2\
Because the updated lists are available online, providers should
ensure they are using the most recently updated lists when screening
customers against these lists.
If no concerns are raised after consulting these lists, the
provider should proceed to sequence screening. If a sequence of concern
is identified, providers should conduct follow-up screening. If there
are concerns after consulting these lists, providers should consider
seeking assistance from the U.S. Government as outlined in Section VII.
B. Foreign Orders
Once an order from a foreign customer is received, the provider
should conduct customer screening.
In addition to complying with the rules described for domestic
orders, all providers who export products from the United States to
international customers must comply with the U.S. export laws,
including the International Emergency Economic Powers Act,\8\ the
Trading with the Enemy Act,\9\ and any implementing U.S. Government
regulations or Presidential Executive orders. Certain transactions with
sanctioned countries may be permitted but may require a license from
OFAC and/or the Department of Commerce's Bureau of Industry and
Security (BIS). Most transactions involving Cuba, Iran, and Sudan are
prohibited. In order to comply with the U.S. export laws and
regulations, providers must first determine whether a given transaction
with a sanctioned country is permitted, and, if not permitted, obtain
any appropriate export licenses or other U.S. Government permissions
prior to exporting any product to sanctioned countries.
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\8\ Visit http://www.treas.gov/offices/enforcement/ofac/legal/statutes/ieepa.pdf for additional information.
\9\ Visit http://www.treas.gov/offices/enforcement/ofac/legal/statutes/twea.pdf for additional information.
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According to U.S. regulations, no U.S. persons or entities may
conduct transactions with individuals or entities on the SDN List
without a license from OFAC. This list is maintained by OFAC. OFAC only
provides a license to deal with individuals on the SDN List in
extremely limited circumstances.\6\
According to U.S. regulations, no U.S. persons or entities may
conduct business transactions with individuals sanctioned by the
Department of State for engaging in proliferation activities.\7\
If no concerns are identified during customer screening or the
checks against the lists delineated above, the provider should perform
sequence screening. In addition to performing sequence screening for
Select Agents and Toxins, providers are also encouraged to perform
sequence screening of orders from foreign customers to determine
whether they are governed by the EAR. As a member of the Australia
Group, the United States requires exporters through the EAR to obtain
export licenses for exports of reading-frame length nucleic acid
sequences from pathogens listed under Export Control Classification
Numbers (ECCNs) 1C351, 1C352, 1C353, and 1C354. The EAR also requires
exporters to obtain licenses for exports of reading-frame length
nucleic acid sequences from pathogens on the Select Agent list not
listed elsewhere on the CCL (ECCN 1C360). The EAR requirements
specifically apply to genetic elements that encode toxins or sub-units
of controlled toxins or genetic elements associated with pathogenicity
of controlled microorganisms. Because the EAR's CCL and the Select
Agents and Toxins list are not identical, separate screening for those
sequences on the CCL is necessary for international orders. The U.S.
Government recommends that in addition to screening for Select Agents
and Toxins, providers use a ``Best Match'' approach to identify
pathogens and toxins on the CCL when an order is placed by an
international customer. If the ordered synthetic nucleic acid is
controlled under ECCN 1C353 and is capable of encoding a protein, an
export license is necessary for all international orders, according to
the EAR.\2\
Even for exported items that do not have a specific entry on the
CCL and are considered under EAR 99 (for which a license is not
required to most destinations), certain individuals and organizations
are prohibited from receiving U.S. exports and others may only receive
goods if they have been licensed. As a result, before filling an
international order for any synthetic nucleic acid that cannot be
classified under an ECCN, providers must consult several lists of such
individuals and organizations according to the EAR. If the customer
appears on any of these lists, additional action is required and an
export license may be necessary, depending on the list.\10\ These lists
include the DPL, the Entity List (EL), and the Unverified List (UL).
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\10\ A general review of export control basics is available at
http://www.bis.doc.gov/licensing/exportingbasics.htm.
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In addition to the SDN List and proliferation sanctions
notifications, providers must not conduct business with persons and
entities on the DPL based on the EAR.\2\ The DPL includes parties that
have been denied export and reexport privileges.
In accordance with the EAR, exports to persons or entities on the
EL require an export license.\2\ The EL contains a list of names of
certain foreign persons--including businesses, research institutions,
government and private organizations, individuals, and other types of
legal persons--that are subject to specific license requirements for
the export, reexport and/or transfer (in-country) of specified items.
On an individual basis, the persons on the EL are subject to licensing
requirements and policies supplemental to those found elsewhere in the
EAR.
The presence of a party on the UL in a transaction is a ``red
flag'' that should be resolved before proceeding with the
transaction.\2\ The UL includes names and countries of foreign persons
who in the past were parties to a transaction with respect to which BIS
could not conduct a pre-license check (PLC) or a post-shipment
verification (PSV) for reasons outside of the U.S. Government's
control. Additional ``red flags'' can be found in Supplement No. 3 to
Part 732 of the EAR.
To avoid violating U.S. laws and regulations, providers should
consult these lists whenever an international customer places an order.
Because the updated lists are available online, providers should ensure
they are using the most recently updated lists when screening customers
against these lists. The U.S. Government recommends that the provider
check the individual placing the order and the individual's affiliated
institution (when applicable) against these lists.
Additionally, U.S. persons or entities may not export, reexport, or
transfer (in-country) an item subject to the EAR without a license if,
at the time of export, reexport, or transfer (in-country) the exporter
knows that the item will be used in the design, development,
production, stockpiling, or use of biological weapons in or by any
country or destination, worldwide.
If any of these checks reveals cause for concern, the provider
should proceed according to the details provided in Section VII.
Additionally, if a sequence of concern is identified after sequence
screening, follow-up screening should occur.
If an order involves an export, according to the EAR, both the
provider
[[Page 62325]]
and customer are required to maintain documentary evidence of the
transaction and are prohibited from misrepresenting or concealing
material facts in licensing processes and all export control
documents.\2\
VII. Contacting the U.S. Government
In cases where follow-up screening cannot resolve an issue raised
by either customer screening or sequence screening, the U.S. Government
recommends that providers contact one of the following agencies for
further information:
Federal Bureau of Investigation (FBI)
If an order turns up `red flags' or includes a sequence of concern
and follow-up screening does not sufficiently clarify the customer's
identity and the order's intended end-use, providers should contact the
Weapons of Mass Destruction (WMD) Coordinator at their nearest FBI
Field Office. Providers should also contact the WMD Coordinator if the
follow-up screening reveals that the customer has no legitimate need
for the order.
CDC and APHIS Select Agent Regulatory Programs (Select Agent Programs)
If necessary, the CDC and APHIS Select Agent regulatory programs
can be contacted through the national Select Agent Web site (http://www.selectagents.gov). The CDC program can be contacted directly via e-
mail at [email protected] or by fax at 404-718-2096. The APHIS program can
be contacted directly via e-mail at
[email protected] or by fax at 301-734-
3652.
Department of Commerce
If sequence screening reveals that an order from an international
customer contains a Select Agent or sequence of concern, providers
should contact the nearest field office of the Department of Commerce's
Office of Export Enforcement. Providers should also contact the Office
of Export Enforcement if they receive an international order from a
country currently subject to a U.S. trade embargo or a customer that is
on one of the proscribed lists described in Section VI. The Department
of Commerce will contact other U.S. Government agencies as necessary.
The supervisory office is in Washington, DC and the phone number is
202-482-1208. Locations and contact information for all field offices
are available at http://www.bis.doc.gov/about/programoffices.htm.
Assistance from an export counselor at the Department of Commerce is
available by calling 202-482-4811.
Scenarios
If providers encounter one of the following scenarios and are
unable to resolve issues raised by customer screening or sequence
screening, they can contact one of the following U.S. Government
agencies for assistance, using the contact information provided above:
1. Provider receives double-stranded synthetic DNA order and a
customer flag (suspicious customer) is identified in customer
screening. Recommend the provider contact the nearest FBI Field Office
WMD Coordinator. FBI contacts other Departments and Agencies, as
appropriate.
2. Provider receives a double-stranded synthetic DNA order that is
for a Select Agent or Toxin. Provider should refer to the Select Agent
Regulations and follow necessary protocols. If necessary, the provider
should contact the appropriate Select Agent Program (CDC or USDA/
APHIS).
a. CDC or APHIS may contact FBIHQ as appropriate.
3. Provider receives a double-stranded DNA order that incorporates
a sequence of concern; follow-up screening reveals no legitimate
purpose \11\ for order or research requirement. Provider contacts the
FBI WMD Coordinator. FBI contacts the CDC or APHIS as appropriate.
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\11\ 18 U.S.C. 175(b) defines criminal prohibitions with respect
to biological weapons as ``Whoever knowingly possesses any
biological agent, toxin, or delivery system of a type or in a
quantity that, under the circumstances, is not reasonably justified
by a prophylactic, protective, bona fide research, or other peaceful
purpose, shall be fined under this title, imprisoned not more than
10 years, or both.''
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4. Provider receives an international double-stranded DNA order
incorporating a Select Agent or Toxin or a sequence of concern and DOC
denies the export license. DOC contacts the FBI as appropriate.
5. Provider receives a double-stranded DNA order from a customer
that is listed on one or more restricted lists, which prohibits the
fulfillment of the order. Provider contacts the FBI WMD Coordinator.
FBI contacts DOC as appropriate.
VIII. Customer and Sequence Screening Software and Expertise
There are a variety software packages that can assist with the
verification of customers and screening against the necessary lists of
proscribed entities. Providers should be aware that commercially
available software packages may not necessarily address all aspects of
customer screening recommended by the U.S. Government.
In addition to a sequence database and screening method,
appropriate sequence screening software must be selected by synthetic
nucleic acid providers. The U.S. Government recommends that synthetic
nucleic acid providers select a sequence screening software tool that
utilizes both a global and local sequence alignment technique; the most
popular algorithm that meets both requirements is the BLAST search
tool. BLAST is available for download for free at the NCBI site.
Similar tools are also freely or commercially available, or could be
designed by the provider to meet their sequence screening needs. By
utilizing such a tool, similarity over the length of the sequence being
screened and the identification of regions that are similar within
longer segments that are not alike are both encompassed in the sequence
screening approach. Specific criteria for the statistical significance
of the hit (BLAST's e-values) or percent identity values will not be
recommended because these details depend on the specific screening
protocol. By utilizing the ``Best Match'' approach, the sequence with
the greatest percent identity over the entire 66 amino acid sequence
should be considered the ``Best Match,'' regardless of the statistical
significance or percent identity.
The U.S. Government recommends that synthetic nucleic acid
providers have the necessary expertise in-house to perform the sequence
screenings, analyze the results and conduct the appropriate follow-up
research to evaluate the significance of dubious sequence matches. Such
follow-up research could include comparing the ordered sequence to
information found in the published literature about Select Agents and
Toxins or with information found in other databases of Select Agents
and Toxins.
The U.S. Government recognizes that continued research and
development on new and improved bioinformatics tools is desirable. As
new methods are developed, U.S. guidance may change accordingly.
IX. Records Retention
The U.S. Government recommends that companies retain electronic
copies of customer orders for at least eight years based on statutory
limitations set forth by U.S. Code of Federal Crimes and Procedures,
Title 18 Section 3286.\4\
The U.S. Government recommends archiving the following information:
Customer (and end-user, if different) information (name, organization,
address, and phone number), order sequence information, and order
[[Page 62326]]
information (date placed and shipped, shipping address, and receiver
name).
The U.S. Government recommends that providers develop, maintain,
and document their sequence screening protocol within company records.
The U.S. Government recommends that providers develop, maintain,
and document protocols to determine if a sequence hit qualifies as a
true sequence of concern.
The U.S. Government recommends that providers keep records of any
follow-up screening, even if the order was ultimately filled.
If an order involves an export, according to the EAR, both the
provider and customer are required to maintain documentary evidence of
the transaction and are prohibited from misrepresenting or concealing
material facts in licensing process and all export control
documents.\2\
X. Appendix to Screening Framework Guidance for Synthetic Double-
Stranded DNA Providers
Summary of Recommendations
The field of synthetic genomics is evolving rapidly. This document
is intended to provide guidance to producers of synthetic genomic
products regarding the screening of orders to ensure that these orders
are filled in compliance with current U.S. regulations and encourage
best practices in addressing any potential biosecurity concerns. The
U.S. Government recommends that all orders for synthetic double-
stranded DNA 200 base pairs (bps) in length or greater be subject to a
screening framework that incorporates both sequence screening and
customer screening.
Customer Screening
The U.S. Government recommends that, for every order, synthetic
nucleic acid providers:
(1) Gather the following information to verify a customer's
identity:
Customer's (and end-user's, if different) full name and
contact information
Billing address and shipping address (if not the same)
Customer's institutional or corporate affiliation (if
applicable)
Name of institution's Biological Safety Officer (if
applicable)
(2) Screen customers against several lists of proscribed entities
(described under the Domestic Orders and Foreign Orders sections).
In cases where the customer is not affiliated with an institution
or firm, the U.S. Government recommends that the provider conduct
follow-up screening.
If a review of customer information reveals one or more `red
flags,' the U.S. Government recommends that providers exercise due
diligence, inquire regarding the circumstances, and verify the end-use
and end-user (see the Follow-Up Screening section).
Sequence Screening
The U.S. Government recommends that:
Nucleic acid sequences be screened using a ``Best Match''
approach to identify nucleic acids that are unique to Select Agents and
Toxins.
For foreign orders, nucleic acids be screened using a
``Best Match'' approach to identify nucleic acids that are unique to
pathogens and toxins on the Commerce Control List.
Sequence screening be performed for both DNA strands and
the resultant polypeptides derived from translations using the three
alternative reading frames on each DNA strand (or six-frame
translation).
Sequence alignment methods should permit the detection of
hidden ``sequences of concern'' as small as 200 bps.
If a customer orders a synthetic nucleic acid that can be
classified as a Select Agent or Toxin, the provider should consult and
must abide by the CDC and USDA/APHIS Select Agent Regulations (42 CFR
73, 7 CFR 331, and 9 CFR 121). In order to produce a regulated Select
Agent or Toxin nucleic acid, the producer must be registered with CDC
or USDA/APHIS.\12\
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\12\ Additional information regarding the CDC and USDA/APHIS
Select Agent Regulations is available at http://www.selectagents.gov.
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The U.S. Government recommends that providers continue to exercise
their due diligence in the investigation of screening hits against non-
Select Agents and Toxins that may raise a biosecurity concern.
Follow-up Screening
When customer screening reveals any `red flags' or sequence
screening identifies a sequence of concern, the U.S. Government
recommends that providers ask for information regarding the customer's
proposed end-use of the order to assess their need and the scientific
legitimacy of their work. If the customer is associated with an
institution or firm, providers should also contact the customer's
biological safety officer, supervisor, lab director or director of
research to verify their identity and need. If the customer is not
affiliated with an institution or firm, providers should also conduct a
literature review of the customer's past research to verify his or her
identity and need.
Domestic Orders
The U.S. Government reminds providers of the following:
According to U.S. regulations, no U.S. persons or entities
may conduct transactions with individuals or entities on the list of
Specially Designated Nationals and Blocked Persons (SDN List) without a
license from the Department of the Treasury Office of Foreign Assets
Control (OFAC).\13\
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\13\ Additional information, including the SDN List, is
available at: http://www.treas.gov/offices/enforcement/ofac/sdn/.
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According to U.S. regulations, no U.S. persons or entities
may conduct business transactions with individuals sanctioned by the
Department of State for engaging in proliferation activities.\14\
---------------------------------------------------------------------------
\14\ Announcements of such sanctions determinations are printed
in the Federal Register and are maintained on the Department of
State's Web site (http://www.state.gov/t/isn/c15231.htm).
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The U.S. Government recommends that providers check domestic
customers against the most recent Department of Commerce Denied Persons
List (DPL).\15\
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\15\ Visit http://www.access.gpo.gov/bis/ear/ear_data.html to
access the most recent Commerce Control List and review the Export
Administration Regulations.
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In order to avoid violating U.S. law, providers are encouraged to
check the individual placing the order and the individual's affiliated
institution (when applicable) against the most recent versions of these
lists of proscribed entities before filling each order.
Foreign Orders
The U.S. Government reminds providers of the following:
All providers who export products from the United States
to international customers must comply with the U.S. export laws,
including the International Emergency Economic Powers Act (IEEPA),\16\
the Trading with the Enemy Act,\17\ and any implementing U.S.
Government regulations or Presidential Executive Orders. Certain
transactions with sanctioned countries may be permitted, but most
require a license from OFAC and/or the Department of Commerce's Bureau
of Industry and Security (BIS). Most transactions involving Cuba, Iran,
and Sudan are prohibited. In order to comply with the U.S. export laws
and regulations, providers must first determine whether a given
transaction with a sanctioned
[[Page 62327]]
country is permitted, and, if not permitted, obtain any appropriate
export licenses or other U.S. government permissions prior to exporting
any product to sanctioned countries.
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\16\ Visit http://www.treas.gov/offices/enforcement/ofac/legal/statutes/ieepa.pdf for additional information.
\17\ Visit http://www.treas.gov/offices/enforcement/ofac/legal/statutes/twea.pdf for additional information.
---------------------------------------------------------------------------
According to U.S. regulations, no U.S. persons or entities
may conduct business transactions with individuals and entities on the
SDN List without a license from OFAC.\13\
According to U.S. regulations, no U.S. persons or entities
may conduct business transactions with individuals sanctioned by the
Department of State for engaging in proliferation activities.\14\
The Export Administration Regulations (EAR) require that
providers have an export license from BIS prior to exporting a
synthetic nucleic acid that is controlled by an Export Control
Classification Number (ECCN) and is capable of encoding a protein.\15\
U.S. persons or entities may not export, reexport, or
transfer (in-country) an item subject to the EAR without a license if,
at the time of export, reexport, or transfer (in-country) the exporter
knows that the item will be used in the design, development,
production, stockpiling, or use of biological weapons in or by any
country or destination, worldwide.\15\
In accordance with the EAR, providers must not conduct
business with persons and entities on the DPL.\15\
In accordance with the EAR, exports to persons or entities
on the Entity List are subject to licensing requirements and policies
in addition to those elsewhere in the EAR.\15\
The presence of a party on the UL in a transaction is a
``red flag'' that should be resolved before proceeding with the
transaction.\15\
In order to avoid violating U.S. laws and regulations, providers
are encouraged to check the individual placing the order and the
individual's affiliated institution (when applicable) against the most
recent versions of these lists of proscribed entities before filling
each order.
The U.S. Government recommends that providers utilize a ``Best
Match'' approach to identify sequences of pathogens and toxins on the
Commerce Control List for international orders. This screen is in
addition to the ``Best Match'' sequence screen for Select Agent and
Toxin sequences.
Contacting the U.S. Government
In cases where follow-up screening cannot resolve concerns raised
by customer screening or sequence screening, or when providers are
otherwise unsure about whether to fill an order, the U.S. Government
recommends that providers contact relevant agencies as described in
Section VII of ``Screening Framework Guidance for Synthetic Nucleic
Acid Providers.''
Customer and Sequence Screening Software and Expertise
Providers should be aware that commercially available customer
screening software packages may not necessarily address all aspects of
customer screening recommended by the U.S. Government.
The U.S. Government recommends that:
Synthetic nucleic acid providers select a sequence
screening software tool that utilizes both a global and local sequence
alignment technique.
Synthetic nucleic acid providers have the necessary
expertise in-house to perform the sequence screenings, analyze the
results, and conduct the appropriate follow-up research to evaluate the
significance of dubious sequence matches.
Records Retention
The U.S. Government recommends that:
Companies retain electronic copies of customer orders for
at least eight years based on the statute of limitations set forth by
U.S. Code Title 18 Section 3286.\18\ The following information should
be archived: Customer (and end-user, if different) information (name,
organization, address, and phone number), order sequence information,
and order information (date placed and shipped, shipping address, and
receiver name).
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\18\ Section 3286 specifies that no person shall be prosecuted,
tried, or punished for any noncapital offense involving certain
violations unless the indictment is found or the information is
instituted within 8 years after the offense was committed. This
statute of limitations applies to Title 18 Section 175(b)
(possession of biological agents with no reasonable justification).
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Providers develop, maintain, and document their sequence
screening protocols within company records.
Providers develop, maintain, and document protocols to
determine if a sequence hit qualifies as a true sequence of concern.
Providers keep records of hits that required follow-up
screening, even if the order was ultimately filled.
If an order involves an export, according to the EAR, both the
provider and customer are required to maintain documentary evidence of
the transaction and are prohibited from misrepresenting or concealing
material facts in licensing processes and all export control
documents.\15\
Dated: November 19, 2009.
Nicole Lurie,
Assistant Secretary for Preparedness and Response.
[FR Doc. E9-28328 Filed 11-25-09; 8:45 am]
BILLING CODE 4150-37-P