24550 Federal Register / 
Pseudomonas syringae pv. syringae and 
Erwinia herhicola carrying in vitro generated 
deletions of all or part of the genes involved 
in ice nuclcation. 
C. Proposed Modification of Section III- 
B-5 
The RAC Large-Scale Review 
Working Group, which met on October 
26, 1962, forwarded to RAC without 
comment a proposal by Dr. Allan Waitz 
of DNAX Corporation (a wholly owned 
subsidiary of Schering-Plough 
Corporation) to amend Section III— B — 5 of 
the NIH Guidelines. Section III— D — 5 falls 
under that part of the Guidelines which 
defines experiments which require IBC 
approval before initiation. Section III— B— 
5 currently reads: 
-B-5. Experiments Involving Mure Thun 10 
Liters of Culture. The appropriate 
containment will be decided by the IBC. 
Where appropriate, the large-scale 
containment recommendations of the NIH 
should be used (4,1 FR 24968). 
Dr. Waitz said greater flexibility in 
scale-up procedures would be gained if 
the IBC could be notified simultaneously 
with initiation of large-scale procedures 
involving E. coli K-12, Saccharomyces 
cerevisiae and Bacillus subtihs host- 
vector systems. He suggested that 
Section III— B— 5 be modified to read as 
follows: 
III— B— 5. Experiments Involving More Than 
tO Liters of Culture. The appropriate 
containment will be decided by the IBC 
except where exempted under Section III— D — 
5. Where appropriate, the large-scule 
containment recommendations of the Nil! 
should be used (45 PR 24968). 
Language in Appendix C, Exemptions 
Under III-D-5, would also be modified 
to reflect this change. The relevant 
paragraphs of Appendix C— II, C — III, and 
C-IV, which deal with exceptions to the 
exemption would be modified to read as 
follows: 
Large-scale experiments (i.e., more than 10 
liters of culture) require IBC notice 
simultaneously with the initiation of 
experiments where IBC-approved practices 
and an IBC-approved Pl-LS containment 
facility will be used. Where these conditions 
are not satisfied, refer to Section III— B — 5. 
The proposal was published in the 
March 4, 1983, Federal Register (48 FR 
9436). During the comment period, no 
comments were received. The RAC 
discussed the proposal at its April 11, 
1983, meeting. By a vote of ten in favor, 
eight opposed, and one abstention, the 
RAC recommended this proposal. 
Because of the close vote and because 
1 regard the present requirements for 
IBC prior approval as prudent and not 
overly restrictive, I do not accept this 
recommendation. 
Vol. 48. No. IOC / Wednesday, June 
D. Proposed Modifications of Physical 
Containment Recommendations for 
Large-Scale Uses of Organisms 
Containing Recombinant UNA 
Molecules (45 FR 24UGB, Federal 
Register of April 11. 108(1) 
1. Proposed Modification of Section 
VII-D-6. Mr. Richard F. Geoghegan of E. 
I. DuPont de Nemours and Company in a 
letter dated July 15, 1982, requested that 
Section VII-D-6 of the Large-Scale 
Recommendations be revised. Section 
VII-D-6 reads as follows: 
VII-D-6 # A closed system used for the 
propagation and growth of viable organisms 
containing recombinant DNA molecules shall 
be operated so that the space above the 
culture level will be maintained at or slightly 
below atmospheric pressure. 
Mr. Geoghegan proposed that Section 
VII-D-6 be modified to read as follows: 
VII-D-6. A closed system used for the 
propagation and growth of viable organisms 
containing recombinant DNA molecules shall 
be operated so that the space above the 
culture level be maintained at no more than 
10 psig. 
He argued that the revision will 
permit fermentations more in line with 
industrial practices (high biomass 
production through efficient oxygen 
transfer) to be conducted without 
compromising safety by operating at 
unnecessarily high vessel pressures. 
However, the RAC Large-Scale Review 
Working Group, at its meeting on 
October 26, 1982, felt the language might 
appropriately be modified, but felt no 
specific pressure limit should be 
indicated as any pressure limit should 
be dependent on the maximum design 
pressure of the system. 
The working group, thus, suggested 
the following language: 
VII-D-6. A closed system used for the 
propagation and growth of viable organisms 
containing recombinant DNA molecules shall 
be operated so that the space above the 
culture level will bg maintained at a pressure 
as low as possible, consistent with equipment 
design, in order to maintain the integrity of 
containment features. 
The Large-Scale Review Working 
Group at its meeting on October 26, 
1982, recommended this language by a 
vote of five in favor, none opposed, and 
no abstentions. 
Both proposed modifications of 
Section VII-D-6 were published for 
comment in the March 4, 1983, Federal 
Register (48 FR 9437). No comments 
were received during the comment 
period. 
The proposals were discussed by the 
RAC at its April 11, 1983, meeting. It was 
pointed out that operation of vessels at 
pressures below or at atmospheric 
pressure may result in poor yield, und 
1, 1983 / Notices 
that the integrity of seals and other 
components must be assured under the 
Large-Scale Recommendations. By a 
vote of nineteen in favor, none opposed, 
and no abstentions, the RAC 
recommended the language proposed by 
the Large-Scale Review Working Group. 
I accept this recommendation. 
2. Proposed Modification of Section 
VII-B-3. Dr. Allan Waitz of DNAZ 
Corporation also proposed amending 
Section VII-B-3 which reads as follows: 
VII-B-3. Sample collection from a closed 
system, the addition of materials to a closed 
system and the transfer of culture fluids from 
one closed system to another shall be done in 
a manner which prevents the release of 
aerosols or contamination of exposed 
surfaces. 
Dr. Waitz suggested that the word 
"prevents" implies an absolute 
condition which at the Pl-LS level is 
neither realistic nor necessary. He 
suggested that the word “minimizes" be 
substituted for the word "prevents." The 
Large-Scale Review Working Group did 
not discuss this proposal at its meeting 
on October 26, 1982. 
The March 4, 1983, Federal Register 
(48 FR 9437) described the proposal. No 
comments were received during the 
thirty day comment period. 
At the April 11, 1983, meeting, RAC 
evaluated the proposal. The RAC 
recommended that in Section VII-B-3 
the word "minimizes" be substituted for 
"prevents" by a vote of ten in favor, four 
opposed, and four abstentions. I accept 
this recommendation. 
E. Proposed Incorporation Into 
Guidelines of Physical Containment 
Recommendations for Large-Scale Uses 
of Organisms Containing Recombinant 
DNA Molecules 
Dr. Allan Waitz of DNAX Corporation 
at the October 26, 1982, meeting of the 
RAC Large-Scale Review Working 
Group proposed that the Physical 
Containment Recommendations for 
Large-Scale Uses of Organisms 
Containing Recombinant DNA 
Molecules (45 FR 24968) be formalized 
by incorporating them into the 
Guidelines as a new appendix. Dr. 
Waitz said industry believes such an 
action would provide a more efficient 
mechanism for further comment or 
change to the Recommendations. He 
expressed industry's concern that failure 
to take such action may leave a 
perceived gap in the overall regulatory 
scheme, thereby, encouraging the 
development of conflicting regulatory 
requirements. 
The Large-Scale Review Working 
Group which met on October 26, 1982. 
forwarded this proposal to the RAC and 
r i3ii 
