[Federal Register Volume 81, Number 73 (Friday, April 15, 2016)]
[Notices]
[Pages 22286-22289]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-08810]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
National Institutes of Health (NIH) Office of Science Policy
(OSP) Recombinant or Synthetic Nucleic Acid Research: Action Under the
NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic
Acid Molecules (NIH Guidelines)
SUMMARY: The NIH OSP is amending portions of the NIH Guidelines in
order to provide investigators with biosafety guidance regarding the
standards for containment of non-human primates (NHPs) in biosafety
level (BL) 4 laboratories and to make such guidance consistent with the
expectations articulated in the Centers for Disease Control and
Prevention (CDC)/NIH Biosafety in Microbiological and Biomedical
Laboratories 5th edition (BMBL). Specifically, the NIH Guidelines will
allow for housing of NHPs in open caging in a dedicated animal holding
room provided there are two physical barriers between that animal
holding room and non-containment space within the laboratory, the
animal holding room has negative air pressure with respect to any
adjacent non-containment corridors, and there are specific
decontamination protocols in place before the door to the animal
holding room is opened to allow for the periodic transfer of new
animals into the room. These amendments do not change the current
containment requirements in the NIH Guidelines but rather offer an
alternative for achieving primary containment without compromising
safety.
In addition, the recertification requirement for biosafety cabinets
in BL4 laboratories is updated in recognition of the technological
standards for modern biosafety cabinets. The NIH OSP also is updating
the validation requirements for equipment responsible for centralized
heat decontamination of liquid effluents in laboratories working with
large animals.
These amendments to the NIH Guidelines will be implemented
immediately upon publication in the Federal Register. These changes
were developed after extensive consultation with biosafety experts,
directors of and principal investigators in BL4 facilities working with
NHPs, and CDC's Division of Select Agent and Toxins (DSAT) leadership
at a public workshop and discussion at a public Recombinant DNA
Advisory Committee (RAC) meeting. Publication in the Federal Register
will inform the scientific and biosafety communities.
FOR FURTHER INFORMATION CONTACT: If you have questions, or require
additional information about these changes, please contact the NIH OSP
by email at [email protected], or telephone at 301-496-9838.
SUPPLEMENTARY INFORMATION: The first three editions of the BMBL and the
NIH Guidelines were consistent in their approach to requiring primary
containment for animal work in BL4 containment laboratories. However,
in the early 1990s, the BMBL was amended and the fourth edition stated
that animals housed in BL4 suit laboratories (i.e., laboratories in
which Class III cabinets are not used but instead personnel wear
positive pressure protective suits) should be housed in a primary
containment system (such as open cages covered with filtered bonnets
and opened in laminar flow hoods or other equivalent containment
systems). This language remains in the current BMBL (5th edition). With
the change in the BMBL, primary containment caging was arguably
preferred but no longer required under BL4 containment. In contrast,
the NIH Guidelines have always required primary containment caging for
all animals in BL4 laboratories.
Non-human primates are social animals and require environmental
enrichment. Researchers in several U.S. BL4 laboratories engaged in NHP
research approached the NIH OSP with concerns that primary containment
caging in BL4 laboratories hindered the creation of an environment that
allowed animals to benefit from adequate social interaction. Also based
on risk assessments and experiences comparing several primary
containment caging systems, the researchers concluded that primary
containment caging may actually create new hazards for laboratory
workers. These findings included interference with observation of the
animals from outside the room leading to more frequent entries into the
BL4 animal room to monitor the animals, and exacerbation of cramped
working conditions created by the additional barriers required by some
containment systems, which increases the difficulty of working in
inflated pressure suits as well as the potential for damage to the
pressure suit. In addition, investigators stated that current BL4
laboratory designs incorporate sophisticated engineering systems, which
provide biosafety protection in a dedicated animal room equivalent to
the primary containment caging required under the NIH
[[Page 22287]]
Guidelines. On March 28, 2014, the NIH OSP, together with the CDC
Division of Select Agents (DSAT), held a meeting with investigators and
biosafety personnel from nine BL4 laboratories in the U.S. and five
international laboratories (agenda and roster available at http://osp.od.nih.gov/office-biotechnology-activities/event/2014-03-28-120000-2014-03-28-211500/primary-containment-non-human-primates-biosafety-level-4-laboratories-challenges-and-best-practices). That meeting was
followed by a discussion at the June 11, 2014, meeting of the NIH RAC
regarding housing of NHPs in BL4 laboratories (a webcast of that
discussion is available at http://videocast.nih.gov/summary.asp?Live=14300&bhcp=1.)
As a result of these discussions and after consultation with CDC
DSAT, the NIH OSP is amending the NIH Guidelines to allow the housing
of NHP in open cages in a dedicated animal room provided certain
conditions as articulated below are met.
In addition, OSP is updating the requirement for testing and
certification of Class I and II biosafety cabinets at BL4 from every
six months to annually, recognizing the technological advances in
biosafety cabinet design and engineering that have occurred over the
period since this performance measure was originally implemented.
Finally, Appendix Q of the NIH Guidelines currently requires that
the centralized heat treatment catch tank system in BL4 large animal
laboratories be validated every 30 days. To carry out this testing
effectively, the system should be near capacity (i.e. ``under load'').
Some laboratories do not use their catch tank systems on a regular
basis; therefore, a mandatory 30 day validation would require them to
demonstrate that the equipment is functioning when it is not in use or
is not at capacity. This will not serve the intended purpose of
demonstrating that the equipment is functioning as intended. Therefore,
validation intervals will need to be set based on the utilization of
the system provided it is done at least once a year.
To implement these changes, the following sections of the NIH
Guidelines are to be amended:
Appendix G-II-D-2-l. currently states:
Appendix G-II-D-2-l. Laboratory animals involved in experiments
requiring BL4 level physical containment shall be housed either in
cages contained in Class III cabinets or in partial containment
caging systems, such as Horsfall units (see Appendix G-III-K,
Footnotes and References of Appendix G), open cages placed in
ventilated enclosures, or solid-wall and -bottom cages placed on
holding racks equipped with ultraviolet irradiation lamps and
reflectors that are located in a specially designed area in which
all personnel are required to wear one-piece positive pressure
suits.
Appendix G-II-D-2-1 is amended as follows with the addition of a
new Appendix G-II-D-2-1-(2) that will address housing of NHPs:
Appendix G-II-D-2-l. Containment for Animal Research
Appendix G-II-D-2-l-(1). Laboratory animals involved in experiments
requiring BL4 level physical containment shall be housed either in
cages contained in Class III cabinets or in partial containment caging
systems, such as Horsfall units (see Appendix G-III-K, Footnotes and
References of Appendix G), open cages placed in ventilated enclosures,
or solid-wall and -bottom cages placed on holding racks equipped with
ultraviolet irradiation lamps and reflectors that are located in a
specially designed area in which all personnel are required to wear
one-piece positive pressure suits.
Appendix G-II-D-2-l-(2). Non-human primates (NHP) may be housed (1)
under the containment conditions described in Appendix G-II-D-2-l-(1)
above, or (2) in open cages within a dedicated animal holding room that
serves as the primary barrier and in which all personnel are required
to wear one-piece positive pressure suits. A room serving as a primary
barrier must be air-tight and capable of being decontaminated using
fumigation. If NHPs are to be contained in a dedicated animal holding
room serving as the primary barrier, the following conditions shall be
met:
(i) Access to the animal holding room from service corridors
outside of the BL4 containment space shall require passage through two
sets of doors, and the inner most door must be an air pressure
resistant (APR) door;
(ii) For any animal holding room considered to be a primary
barrier, APR door(s) providing direct ingress from the exterior service
corridor shall be fitted with appropriate and redundant lock-out
mechanisms to prevent access when the animal holding room is
contaminated and in use. There should be more than one mechanism to
ensure that this primary barrier door cannot be opened when the animal
room is contaminated and the APR door shall not serve as an emergency
exit from the BL4 laboratory. The APR door shall be appropriately
tested to demonstrate that in the closed, locked-out mode, the door
provides an air-tight barrier proven by pressure decay testing or other
equivalent method;
(iii) Any door(s) allowing access into a corridor from which there
is direct ingress to an animal holding room must be fitted with either
(1) an APR door or (2) a non-APR door, providing directional airflow is
maintained from the laboratory corridor space into the animal room. For
the purpose of fumigation, animal rooms equipped with non-APR doors
opening into the adjacent interior corridors shall be considered one
space (i.e., areas between air-tight doors shall be fumigated
together).
(iv) Any door(s) used for access to the service corridor (the
secondary barrier) shall be self-closing and of solid construction,
designed not to corrode, split or warp;
(v) Access to the service corridor inside the secondary barrier
shall be restricted and strictly controlled when animal rooms are in
use. Whenever possible, the secondary barrier door(s) should be fitted
with safety interlock switches designed to prevent it from opening when
an animal holding room door (the primary barrier) is opened following
room decontamination; if interlock devices cannot be used, specific
administrative procedures shall be implemented to control access to the
service corridor;
(vi) The service corridor shall maintain a negative pressure
(inward directional airflow) relative to adjoining traffic corridors;
(vii) Prior to fumigation of the animal holding room, cages should
be removed for autoclaving or chemical decontamination.
(viii) Caging should be chosen to reduce the amount of animal
detritus that can be thrown out of the cage and onto the floor of the
animal holding room;
(ix) The flow of personnel, material and equipment should be
directed in order to minimize the spread of contamination from the
animal holding room into adjacent areas of the laboratory.
(x) Following animal room decontamination, safeguards involving the
use of personal protective equipment and appropriate administrative
controls shall be implemented for the safe retrieval of biological
indicators in order to prevent the spread of infectious agents in the
event of a decontamination failure.
With regard to the frequency of class II biosafety cabinet
recertification and testing, the NIH Guidelines require
recertification/testing of biosafety cabinets at six-month intervals.
However, modern biosafety cabinet
[[Page 22288]]
design specifications incorporate continuous electronic and physical
monitoring systems that track multiple operational parameters such as
pressure differential, air flow velocity and plenum pressure with added
capabilities for remote control and monitoring. Continuous performance
monitoring and redundant safety features obviate the need for frequent
testing of modern biosafety cabinets under normal conditions of use.
Also the testing of biosafety cabinets in biomedical high containment
(BL4) laboratories entails a complete shutdown of the laboratory for
decontamination with appropriate sterilants to allow technicians to
access the equipment safely. This procedure increases risks to
laboratory staff working with the sterilants (often in the form of
toxic gasses) and requires a halt to all research activities for an
extended period of time depending on the number of cabinets to be
tested or recertified. The NIH is in agreement with the recommendation
of the BMBL that class II biosafety cabinets be tested and certified at
least annually, with the understanding that retesting may have to be
performed as needed at the discretion of the Institutional Biosafety
Committee (IBC), if for example, equipment is moved or subject to
unusual conditions of use.
Appendix G-II-D-4-p currently states:
Appendix G-II-D-4-p. The treated exhaust air from Class I and II
biological safety cabinets may be discharged into the laboratory
room environment or the outside through the facility air exhaust
system. If exhaust air from Class I or II biological safety cabinets
is discharged into the laboratory the cabinets are tested and
certified at six-month intervals. The exhaust air from Class III
biological safety cabinets is discharged, without recirculation
through two sets of high efficiency particulate air/HEPA filters in
series, via the facility exhaust air system. If the treated exhaust
air from any of these cabinets is discharged to the outside through
the facility exhaust air system, it is connected to this system in a
manner (e.g., thimble unit connection (see Appendix G-III-L,
Footnotes and References of Appendix G)) that avoids any
interference with the air balance of the cabinets or the facility
exhaust air system.
Appendix G-II-D-4-p is amended as follows:
Appendix G-II-D-4-p. The treated exhaust air from Class I and II
biological safety cabinets may be discharged into the laboratory room
environment or the outside through the facility air exhaust system. If
exhaust air from Class I or II biological safety cabinets is discharged
into the laboratory the cabinets are tested and certified at minimum on
a yearly basis. More frequent testing and certification, based on the
amount of use or other safety factors, shall be left to the discretion
of the IBC. The exhaust air from Class III biological safety cabinets
is discharged, without recirculation through two sets of high
efficiency particulate air/HEPA filters in series, via the facility
exhaust air system. If the treated exhaust air from any of these
cabinets is discharged to the outside through the facility exhaust air
system, it is connected to this system in a manner (e.g., thimble unit
connection (see Appendix G-III-L, Footnotes and References of Appendix
G)) that avoids any interference with the air balance of the cabinets
or the facility exhaust air system.
With regard to the periodic biologic validation of the centralized
heat treatment process for all BL3 and BL4 facilities, the NIH
Guidelines requires that this process be performed every 30 days while
the BMBL recommends at least an annual biological validation. Similar
to biosafety cabinets, modern catch tank systems for heat treatment of
all laboratory effluents have also become more sophisticated and now
incorporate redundant monitoring systems to track temperature and
pressure parameters during each heat treatment cycle. In addition it
should be noted that proper validation of the heat treatment catch tank
system requires that testing be performed when the system is at or near
capacity (i.e. ``under load'')--more frequent validation of a heat
treatment system that is below capacity may not serve the intended
purpose of demonstrating that the equipment is functioning as intended.
An additional margin of safety is achieved by monitoring sterilization
cycle parameters on a routine basis. We are, therefore, in agreement
with the recommendation of the BMBL that validation be performed as
frequently as necessary at the discretion of the IBC and at least once
annually to ensure that the centralized effluent heat treatment system
is performing as intended under the established process parameters.
This amendment shall apply to heat treatment systems used in both large
animal BL3 and BL4 facilities.
For large animal BL3 laboratories, the requirement for
decontamination and inactivation (BL3-N) found at Appendix Q-II-C-1-b-
(5) currently states:
Appendix Q-II-C-1-b-(5). Liquid effluent from containment
equipment, sinks, biological safety cabinets, animal rooms, primary
barriers, floor drains, and sterilizers shall be decontaminated by
heat treatment before being released into the sanitary system. The
procedure used for heat decontamination of liquid wastes shall be
monitored with a recording thermometer. The effectiveness of the
heat decontamination process system shall be revalidated every 30
days with an indicator organism.
Appendix Q-II-C-1-b-(5) is amended as follows:
Appendix Q-II-C-1-b-(5). Liquid effluent from containment
equipment, sinks, biological safety cabinets, animal rooms, primary
barriers, floor drains, and sterilizers shall be decontaminated by heat
treatment before being released into the sanitary system. The procedure
used for heat decontamination of liquid wastes shall be monitored with
a recording thermometer. The effectiveness of the heat decontamination
process system shall be revalidated at minimum on a yearly basis with
an indicator organism. More frequent validation, based on the amount of
use or other safety factors, shall be left to the discretion of the
IBC.
For large animal BL3 laboratories, the requirement for animal
facilities (BL3-N) found at Appendix Q-II-C-2-h currently states:
Appendix Q-II-C-2-h. Liquid effluent from containment equipment,
sinks, biological safety cabinets, animal rooms, primary barriers,
floor drains, and sterilizers shall be decontaminated by heat
treatment before being released into the sanitary system. The
procedure used for heat decontamination of liquid wastes shall be
monitored with a recording thermometer. The effectiveness of the
heat decontamination process system shall be revalidated every 30
days with an indicator organism.
Appendix Q-II-C-2-h is amended as follows:
Appendix Q-II-C-2-h. Liquid effluent from containment equipment,
sinks, biological safety cabinets, animal rooms, primary barriers,
floor drains, and sterilizers shall be decontaminated by heat treatment
before being released into the sanitary system. The procedure used for
heat decontamination of liquid wastes shall be monitored with a
recording thermometer. The effectiveness of the heat decontamination
process system shall be revalidated at minimum on a yearly basis with
an indicator organism. More frequent validation, based on the amount of
use or other safety factors, shall be left to the discretion of the
IBC.
For large animal BL4 laboratories, the requirement for
decontamination and inactivation (BL4-N) found at Appendix Q-II-D-1-b-
(9) currently states:
Appendix Q-II-D-1-b-(9). Liquid effluent from containment
equipment, sinks, biological safety cabinets, animal rooms, primary
barriers, floor drains, and sterilizers shall be decontaminated by
heat treatment before being released into the sanitary
[[Page 22289]]
system. Liquid wastes from shower rooms and toilets shall be
decontaminated with chemical disinfectants or heat by methods
demonstrated to be effective. The procedure used for heat
decontamination of liquid wastes shall be monitored with a recording
thermometer. The effectiveness of the heat decontamination process
system shall be revalidated every 30 days with an indicator
organism. Liquid wastes from the shower shall be chemically
decontaminated using an Environmental Protection Agency-approved
germicide. The efficacy of the chemical treatment process shall be
validated with an indicator organism. Chemical disinfectants shall
be neutralized or diluted before release into general effluent waste
systems.
Appendix Q-II-D-1-b-(9) is amended as follows:
Appendix Q-II-D-1-b-(9). Liquid effluent from containment
equipment, sinks, biological safety cabinets, animal rooms, primary
barriers, floor drains, and sterilizers shall be decontaminated by heat
treatment before being released into the sanitary system. If required
by design, regulation, local ordinance or policy, liquid wastes from
shower rooms and toilets shall be decontaminated with chemical
disinfectants or heat by methods demonstrated to be effective. The
procedure used for heat decontamination of liquid wastes shall be
monitored with a recording thermometer. The effectiveness of the heat
decontamination process system shall be revalidated at minimum on a
yearly basis with an indicator organism. More frequent validation,
based on the amount of use or other safety factors, shall be left to
the discretion of the IBC. If required by design, regulation, local
ordinance or policy, liquid wastes from the shower shall be chemically
decontaminated using an Environmental Protection Agency-approved
germicide. The efficacy of the chemical treatment process shall be
validated with an indicator organism. Chemical disinfectants shall be
neutralized or diluted before release into general effluent waste
systems.
For large animal BL4 laboratories, the requirement for animal
facilities (BL4-N) found at Appendix Q-II-D-2-i currently states:
Appendix Q-II-D-2-i. Liquid effluent from containment equipment,
sinks, biological safety cabinets, animal rooms, primary barriers,
floor drains, and sterilizers shall be decontaminated by heat
treatment before being released into the sanitary system. Liquid
wastes from shower rooms and toilets shall be decontaminated with
chemical disinfectants or heat by methods demonstrated to be
effective. The procedure used for heat decontamination of liquid
wastes shall be monitored with a recording thermometer. The
effectiveness of the heat decontamination process system shall be
revalidated every 30 days with an indicator organism. Liquid wastes
from the shower shall be chemically decontaminated using an
Environmental Protection Agency-approved germicide. The efficacy of
the chemical treatment process shall be validated with an indicator
organism. Chemical disinfectants shall be neutralized or diluted
before release into general effluent waste systems.
Appendix Q-II-D-2-i is amended as follows:
Appendix Q-II-D-2-i. Liquid effluent from containment equipment,
sinks, biological safety cabinets, animal rooms, primary barriers,
floor drains, and sterilizers shall be decontaminated by heat treatment
before being released into the sanitary system. If required by design,
regulation, local ordinance or policy, liquid wastes from shower rooms
and toilets shall be decontaminated with chemical disinfectants or heat
by methods demonstrated to be effective. The procedure used for heat
decontamination of liquid wastes shall be monitored with a recording
thermometer. The effectiveness of the heat decontamination process
system shall be revalidated at minimum on a yearly basis with an
indicator organism. More frequent validation, based on the amount of
use or other safety factors, shall be left to the discretion of the
IBC. If required by design, regulation, local ordinance or policy,
liquid wastes from the shower shall be chemically decontaminated using
an Environmental Protection Agency-approved germicide. The efficacy of
the chemical treatment process shall be validated with an indicator
organism. Chemical disinfectants shall be neutralized or diluted before
release into general effluent waste systems.
Dated: April 9, 2016.
Lawrence A. Tabak,
Deputy Director, National Institutes of Health.
[FR Doc. 2016-08810 Filed 4-14-16; 8:45 am]
BILLING CODE 4140-01-P