/ Vol. 66, No. 138 / Thursday, July 18, 1991 / Notices 
i 33178 Federal Re gister 
‘h — - — 
I ' animals) for claims about the efficacy 
i and safety of the proposed, system for 
I gene delivery and explain why the 
model(s) chosen is (are) the most 
I I appropriate.” 1 ' j ■ 
J This request was pubDshsd for 
comment in the Federal Renter on 
' .March 7, 1991 (56 FR 9707) and amended 
on March 12, 19M (58 FR 10441). 
During the Human Gene Therapy 
Subcommittee meeting of April 5, 1991, 
[the subcomndttee recommended the 
j foUowir^ text change' In the Points to 
\ Consider : ' - 
, , <( .. - ; V - • ■ • V ' ' • ‘ 
ii i-B-2. Preciici^ littidi^ including risk - 
; asaessmrat atuidi^ Ptovide i«alta that 
! demonstrate the t^ety, efficacy, and 
I feasibility of the propos^ proosdures using 
I animal and/or cell culture model sj'stems, 
and explain why the models chosen are the 
I most appropriate. 
The request was published for 
I comment in the Federal Register on 
April 29. 1991 (56 FR 19776). 
At the meeting of May 30-31. 1991, the 
I Redombinant DNA Advisory Conunittee 
I considered the amendment to the Points 
j to Consider. After discussion, the RAC, 
I by a vote of 17 in favor. 1 opposed, and 
;| no abstentions, approved the following 
text : . ; 
1-6-2. Preclinical studies, induding risk 
assessment studies. Provide results that 
I demonstrate the safety, efficacy, and 
feasibility of the proposed procedures using 
animal and/or cell ^ture model sy'stems, 
and explain why the models chosen ere 
^ eppropriatc for the protocol. 
I accept this recommendation, and the 
Points to Consider will be amended 
j accordingly. 
R. SUMMARY OF ACTION’S 
: A. Amendment of Appendix K of the 
“NIH Guidelines " 
The amendment of Appendix K reads 
as follows: 
Appendix K. Physical Containment for 
Large-Scale Uses of Organisms 
' Containing Recombinact DNA 
' Molecules 
This part of the Guidelines specifies ' 
physical contairunent guidelines for 
large-scale (greater than 10 liters of 
• culture) research or production involving 
viable organisms containing 
j recombinant DNA molecules. It shall 
I apply to large-scale research or 
produebon activities as specified in 
section III— B-5 of the Guidelines. It is 
important to note that this appendix 
addresses only the bioloi- ’ hazard 
' associated with organisr.. .ontaim'ng 
recombinant DNA. Other hazards 
i secompanjing the large scale cultivation 
of such organisms (e.g.. toxic properties 
of products; physical, mechanical and 
chemical aspects of downstream 
processing] are not addressed and must 
be considered separately, albeit in 
conjunction with this appendix. 
Ail provisions of the Guidelines shall 
apply to large-scale research or . 
production activities with the following 
modifications: 
■ • Appendix k shall replace appendix 
G when quantities in excess of 10 hters 
of culture are involved in research or ■ . ; 
production. 
• The institutions ahall appoint a 
Biolo^cal Safety Officer (BSO) if it 
. engages in large-scale rMearch. or 
production activities involving viable 
organisms containing recombinant DNA 
molecules. The duties of the BSO ahall 
include those specified in section IV-B-4 
of the Guidelines. 
. • *rhe institution shall establish and 
maintain a health surveillance program 
for personnel engaged in large-scale 
research or production activities 
involving viable organisms containing 
recombinant DNA molecules which 
require BL3 containment at the 
laboratory scale. The program shall 
include: {^assignment and periodic 
physical and medical examinations; 
coUection, maintenance and analysis of 
serum species for monitoring serologic 
changes that may rcsiilt fiom the 
employee’s work experience: and 
provdsions for the investigation of any 
- serious, unusual or extended illnesses of 
emplo 3 'ees to deter min e possible 
occupational origin. 
Appendix K-I. Selection of Physical 
Containment Levels 
The selection of the physical 
containment level required for 
recombinant DNA research or 
production involving more than 10 liters 
of culture is based on the containment 
guidelines established in part in of ffie 
Guidelines. For purposes of large-scale 
research or production, four physical 
containment levels are established. The 
four levels set containment conditions at 
those appropriate for the degree of _ 
hazard to health or the environment 
posed by the organism, judged by 
experience with lar organisms 
unmodified by recombinant DNA 
techniques and consistent with good 
large scale practices. These are referred 
to as GLSP, BLl-LS, EL2-LS, and BL3- 
LS. The GLSP (Good Large-Scale 
Practice) level of physical containment . 
is recommended for large-scale research 
or production involving viable, non- 
pathogenic, end non-toxigehic , ; 
recombinant strains derived from host 
organisms that have an extended history 
of safe large scale use. Likewise, the 
GLSP level of physical containment is 
recommended for organisms such as 
those included in Appendix C that have 
built-in envirorunental limitations that 
permit optimum growth in the large 
scale setting but limited survival without 
adverse consequences in the 
environment For those organisms that 
do not qualify for GLSP. the BLl-LS 
(Biosafety Level 1-Large-Scale) level of 
physical containment is recommended 
for large-scale research or production of 
viable organisms containing 
recombinant DNA modeodes t^t 
require BLl containment at the ' ' - 
laboratory scale. TheBL2-4j5 (Bio^ety 
Level 2-Laxg^Scale) level of physical 
containment is reqnir^ for large-scale 
researdi or pr^uction of viable . 
organisms containing recombinant DNA 
molecules that require BL2 containment 
at the laboratory scale. *rhe BL3-LS 
(Biosafety Level 3-Laige^Scale) level of 
physical containment is required for 
large-scale research or production of 
viable organisms containing 
recombinant DNA molecules that 
require BL3 containment at the 
lalmratory scale. No provisions are : 
made for large-scale reseat or 
prodnetion of viable organisms ' - 
containing recombinant DNA moler^es 
that require BL4 containment at the 
laboratory scale. If necessary, these 
requirements will be established by NIH 
on an Individual basis.' 
Appendix K-IL GLSP Level 
Appendix K-II-A. Institutional codes 
of practice shall be formulated and 
implemented to assure adequate control 
of health and safety matters. 
Appendix K-TI-B. Written instructio!is 
end training of persormel shall be 
provided to assure that cultures of 
viable organisms contaming 
recombinant DNA molecules are 
handled prudently and that the 
workplace is kept clean end orderly. 
Appendix K-D-C. In the interest of 
good personal hygiene, facilities (e.g., 
handwashing sink, shower, changing 
room) and protective clothing (e.g., 
uniforms, laboratory coats] shall be 
provided that are appropriate for the 
risk of exposine to viable organisms 
containing recombinant DNA molecules. 
In addition, eating, drinking, smoking, 
applying cosmetics and mouth pipetting 
shall be prohibited in the work area. 
Appendix K-II-D. Cultures of viable 
organisms containing recombinant DNA 
molecules shall be handled in facilities 
intended to safeguard health during 
. work with microorganisms that do not 
require contairunent 
Appendix K-II-E. Discharges 
containing viable recombinant 
organisms shall be handled in 
tL^ Recombinant DNA Research. Volume 14 
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