Method of conveying liquid materials and device for the automated elution of a radionuclidic generator

The invention relates to a method of conveying liquid materials in closed systems without mutual contamination, comprising flushing the conduit with an inert gas between introduction of the materials into said conduit and using a peristaltic pump for introducing said materials, in which after each flushing operation for a moment said pump is made to rotate in the reverse direction. The invention further relates to a method for the automated elution of a radionuclide generator and delivery of a radiopharmaceutical liquid, in particular a Tc99m-pertechnetate solution, whereas said above method is used, and to a device for performing said method for elution and delivery of a radiopharmaceutical liquid.

The invention relates to a method of conveying liquid materials in closed 
systems without mutual contamination. 
Especially in hospitals and clinics often hazardous liquid materials are 
handled. Preferably such materials are kept in closed systems as much as 
possible to diminish the risk of contamination of the environment, 
including the attendant personnel, with such materials. It is always 
difficult to avoid contamination of such liquid materials with other 
liquid materials, e.g. rinsing fluids, or, vice versa, of these rinsing 
fluids with such hazardous liquid materials in closed systems. In the 
former case undesired dilution of the hazardous liquid material, e.g. a 
pharmaceutical liquid, takes place, in the latter case the rinsing fluid 
is no longer environmentally unsuspected. Conventionally the system is 
flushed with an inert gas, e.g. nitrogen, to remove the first liquid 
material as far as possible before introducing the second liquid material. 
More in particular the present invention relates to a method as mentioned 
in the opening paragraph, comprising the steps of (i) introducing a first 
liquid material into a main conduit through a first inflow conduit 
provided with a first valve, (ii) closing said first valve and flushing 
said main conduit with an inert gas, (iti) stopping the flushing operation 
and introducing a second material into said main conduit through a second 
inflow conduit provided with a second valve, (iv) closing said second 
valve and repeating said flushing operation, and (v), optionally after 
introducing in a corresponding manner a third liquid material through a 
third inflow conduit with valve, repeating the above operations. It has 
been observed, however, that after the flushing operation an aliquot of 
the liquid material, just introduced into the main conduit, is still 
present between the valve and the connection between inflow conduit and 
main conduit, said aliquot with its convex outer surface projecting into 
the main conduit. Part of this aliquot is entrained by the other liquid 
material, next introduced into the main conduit, and consequently 
contaminates this latter liquid material. 
According to the present invention it has now been found, that this problem 
can be avoided by using a peristaltic pump for the introduction of the 
liquid materials into the main conduit and by making said pump to rotate 
for a moment in the reverse direction after each flushing operation. By 
taking the above measures, mutual contamination of the liquid materials 
can be avoided completely. Peristaltic pumps are to be understood to 
comprise tube pumps. 
It will be clear from the above, that the method of the invention is 
intended in particular for conveying liquid materials, one of which is a 
pharmaceutical liquid, especially a radiopharmaceutical liquid. A 
radiopharmaceutical liquid is notoriously hazardous for the environment. 
In general the other liquid will be a rinsing liquid, intended for 
removing the radioactivity from the closed system, i.e. the main conduit, 
as completely as possible. 
The above method according to the present invention is pre-eminently 
suitable for use in an automated system for elution and delivery of 
radiopharmaceutical liquids. Consequently, the present invention also 
relates to a method for the automated elution of a radionuclide generator 
and delivery of a radiopharmaceutical liquid, in particular a 
Tc99m-pertechnetate solution, in a generator-eluting and delivery device, 
comprising a mutually connected solvent reservoir, radionuclide generator, 
pump means, eluate reservoir and delivery station, said method comprising 
the steps of (a) rinsing of the interconnecting means by flushing said 
means with a solvent, (b) program-controlled elution of said generator 
with a predetermined quantity of said solvent and transfer of the 
resulting eluate to said eluate reservoir, the radioactivity of the eluate 
in the reservoir being continuously monitored, (c) program-controlled 
discharge of a predetermined quantity of the eluate and, if desired, 
simultaneously a predetermined quantity of said solvent for diluting 
purposes into said delivery station, from which a controlled quantity of a 
radiopharmaceutical liquid can be dispensed into a vial. Such a 
generator-eluting and delivery device is described in the European patent 
specification 0141800 and, in particular for dispensing a 
Tc99m-pertechnetate solution, in a publication by Fueger et al in Nucl. 
Med. Comm. 8, 1987, 733-749. This device, marketed under the trade name 
Elumark.sup.(R), is particularly intended for dispensing 
Tc99m-pertechnetate in a vial comprising a substance to be radiolabelled 
with Tc99m. Examples of such substances are certain phosphonates, 
colloids, complex-forming ligands, peptides and biological macro-molecules 
such as proteins. 
It has been observed, however, that by employing the above-described device 
for the labelling of certain substances as defined above, serious 
labelling problems occur, as are expressed in low and/or fluctuating 
labelling yields. Surprisingly it has been found, that the presence of 
even small traces of disinfecting or sterilizing substances which are used 
in disinfecting the eluate reservoir, the tubings and the pump of the 
above device at the beginning and the end of the daily routine, can 
dramatically influence the labelling yield. Examples of such substances 
which are usually employed for disinfecting purposes are alcohols, in 
particular propanol, aqueous hydrogen peroxide solution and aqueous sodium 
hypochlorite solution. 
The influence of the presence of traces of propanol on the elution yield 
and consequently on the labelling yield is convincingly demonstrated in 
Applicant's copending and non-prepublished European patent application 
91200555.0. The influence of sodium hypochlorite on the labelling yield is 
demonstrated by the following experiments. Kits are labelled with Tc99m in 
an automated generator-eluting and delivery device as described above, 
wherein the tubing has been disinfected by using 5% w/v sodium 
hypochlorite solution, compared to normal saline flushing. The labelling 
yields are determined, using ITLC. The following results are obtained: 
______________________________________ 
labelling yield 
preparation normal NaOCl 
______________________________________ 
Tc99m-MAG3 97.2 45.6 
Tc99m-HMDP 98.7 44.8 
Tc99m-DTPA 99.3 99.3 
Tc99m-DMSA 100.0 100.0 
Tc99m-HSA 96.9 96.4 
______________________________________ 
The above kit preparations comprise as the substances to be labelled: 
mercaptoacetylglycylglycylglycine (MAG3), hydroxymathylene diphosphonate 
(HMDP), diethylenatriamine pentaacatic acid (IYrPA), dimarcaptosuccinic 
acid (DMSA) and human serum albumin (HSA). As will be apparent from the 
above results, the disinfection with a NaOCl-solution has a disastrous 
effect on the labelling of two kit preparations, viz Tc99m-MAG3 and 
Tc99m-HMDP; apparently the other kit preparations, which are not affected 
by the disinfectant, are less sensitive. There exists also a serious risk, 
what traces of the disinfectant are present in the kit preparation after 
the labelling procedure and then will be injected into the patient. 
The above-described known device has a further disadvantage in that it can 
be used for the labelling of more than one kit preparation only after 
various manipulations. As a matter of fact, after the dispensing procedure 
the labelline vial should be detached from the delivery station and a next 
vial should be attached. Between detachman end attachment the risk of air 
oxygen contamination of the interior of the device and of compromising the 
sterility is not excluded. 
It is therefore a further object of the present invention to provide a 
method for the automated elution of a radionuclide generator and delivery 
of a radiopharmaceutical liquid, in particular a Tc99m-pertechnetate 
solution, in a generator-eluting and delivery device, as described 
hereinbefore, wherein the above disadvantages do not occur. 
This object can be achieved by a method, comprising the steps of (a) 
rinsing of the interconnecting means by flushing said means with a 
solvent, (b) program-controlled elution of said generator with a 
predetermined quantity of said solvent and transfer of the resulting 
eluate to said eluate reservoir, the radioactivity of the eluate in the 
reservoir being continuously monitored, (c) program-controlled discharge 
of a predetermined quantity of the eluate and, if desired, simultaneously 
a predetermined quantity of said solvent for diluting purposes into said 
delivery station, from which a controlled quantity of a 
radiopharmaceutical liquid can be dispensed into a vial, said method being 
characterized according to the present invention in that: 
a peristaltic pump is used as said pump means; 
an inert gas supply is connected to the device; 
between steps (a) and (b) and between steps (b) and (c) the interconnecting 
means are flushed with inert gas and subsequently for a moment said pump 
is made to rotate in the reverse direction, as claimed in claim 1; and 
step (c) is repeated, preceded by a flushing operation and following 
reverse pumping operation. 
By using a peristaltic pump and an inert gas supply any mutual 
contamination of fluids conveyed in the device, e.g. eluate and solvent or 
eluent (generally saline solution), can be avoided. As described 
hereinbefore, a short rotation of the pump in the reverse direction 
following the inert gas flush eliminates any such mutual contamination. 
The system, using an integrated inert gas supply, allows the dispensing of 
the radiopharmaceutical liquid into a great number of vials without 
intermediate detachment and attachment of the vials, so without any 
manipulations. The repetition of this dispensing step, viz. the above step 
(c), is, of course, program-controlled, warranting an accurate 
radioactivity and quantity of the delivered and dispensed 
radiopharmaceutical liquid. The computer program allows an individual 
selection of radioactivity and quantity for each separate vial. 
The use of a peristaltic pump, viz. a tube pump, in a device for eluting a 
radionuclide generator is known from U.S. Pat. No. 3,898,044. The device 
described in this patent, however, is not intended for the automated 
elution and delivery. In addition, said publication does not mention or 
suggest the favourable use of such a pump together with inert gas flushing 
in order to avoid mutual contamination of fluids in the device. 
The invention also relates to a device for performing the method as defined 
above, comprising in addition to a program-control unit: a solvent 
reservoir, a radionuclide generator, a pump means, an eluate reservoir 
externally provided with a radioactivity-monitoring facility, and a 
delivery station, in a mutually connected condition constituted by a 
disposable tubing provided with valves. According to the present 
invention, this device is characterized in that: 
said pump means is a tube pump, 
an inert gas supply is additionally connected to the device, and 
the disposable tubing is provided with tube-clamping valves. 
The use of a tube pump, disposable tubing and tube-clamping valves, e.g. 
pressure valves, in the device of the invention, is particularly 
favourable in that is often the opportunity to replace the pump tubes and 
the disposable tubing as a single unit together with the generator. This 
still better guarantees the sterility of the system, because the liquids 
conveyed in the device are only in contact with the interior of the 
sterilized tubings. This as opposed to the device described above and 
marketed as Elumark.sup.(R), wherein a fluid-contact pump is used, viz. a 
Hamilton dilutor, and wherein fluid-contact valves are used. The used 
clamping valves require an accurate choice of the tubing material and wall 
thickness, as well as an exactly adjusted clamping stroke, to avoid any 
sticking or distortion of the tubes at the clamping area during use of the 
device. 
In said Elumark.sup.(R) device the radioactivity of the eluate is monitored 
by using a semi-conductor. Such a semi-conductor, however, should be 
recalibrated from time to time due to aging effects. Further in this known 
device the quantity of the eluate in the eluate reservoir is measured by 
its volume. 
As an extra aspect of the present invention, it has been found, that 
recalibration of the detector can be avoided by using an ionization 
chamber instead of a semi-conductor. In addition, an ionization chamber 
can be situated around the eluate reservoir and therefore allows a 
particularly accurate measuring of the radioactivity of the contents 
thereof. In addition, if desired, the eluate reservoir may be positioned 
on a balance to measure the quantity of eluate in said reservoir by 
weighing. Weighing is a more accurate method of determining the quantity 
of a certain liquid than measuring the volume, as in the known device. 
Preferably the device of the present invention is provided with a 
controlled inflow facility to maintain a slight overpressure of inert gas 
in the device. A slight overpressure is favourable to avoid any 
environmental contamination of the interior of the device. 
In a pre-eminently favourable embodiment the device of the present 
invention is constructed in such a way, that the delivery station 
comprises a plurality of program-controlled, sequentially opened exit 
ports, each of which is connectible to a vial. This facility, avoiding any 
risk of the simultaneous opening of more than one exit port, is included 
in the computer program.

DETAILED DESCRIPTION OF THE INVENTION 
The invention will now be described in greater detail with reference to the 
drawings, in which FIG. 2 is a simplified scheme, showing the most 
relevant functional parts of a device for elution and delivery of a 
Tc99m-pertechnetate solution, according to the invention, and in which 
FIG. 1 shows in more detail a part of the tubing of the same device. 
The tubing portion shown in FIG. 1 comprises a main conduit 15, to which 
two inflow conduits 16 and 17, respectively, both provided with valves (12 
and 14, respectively), are connected. The main conduit is also provided 
with a valve 11 and is connected to a nitrogen source. Inflow conduit 16 
is fed by one fluid, e.g. a radiopharmaceutical liquid such as a 
Tc99m-pertechnetate solution, in the direction of arrow A. 
Inflow conduit 17 is fed by another fluid, e.g. a rinsing fluid such as a 
saline solution, in the direction of arrow B. After opening of valve for 
example, said saline solution can be pumped in the direction of the arrows 
into the main conduit. Fluid supply is stopped by closing valve 14. After 
opening valve 11 nitrogen can be flushed through the main conduit to 
remove the saline solution therefrom. After nitrogen flush an aliquot of 
said saline solution remains present between the connection 13, between 
main conduit and inflow conduit 17, and the valve 14, said aliquot 
projecting with its convex outer surface (position "a") into the main 
conduit. When the tube pump (not shown in FIG. 1) is made to rotate in the 
reverse direction (valve 11 opened), the outer surface of this aliquot of 
liquid changes to position "b". Now the valve 11 is closed, valve 12 is 
opened and the Tc99m-pertechnetate solution can be pumped in the direction 
of the arrows into the main conduit. Entraining of an aliquot of the 
saline solution by the pertechnetate solution is completely avoided and 
the fluid is not contaminated. 
The simplified scheme shown in FIG. 2 comprises in addition to an N.sub.2 
source (N.sub.2): a solvent or eluent reservoir 18 with a saline solution, 
a tube pump 19, an eluate reservoir 20, externally provided with a 
radioactivity-monitoring facility in the form of an ionization chamber and 
positioned on a balance (both not shown in the caps figure), an air valve 
21 with a bacterial filter, a Mo99-Tc99m generator 22, and a delivery 
station 23, to which a waste bottle w and kit vials k.sub.1 . . . k.sub.n 
are connected. The various parts of the device are mutually connected by 
disposable tubing provided with tube-clamping or pressure valves: 24, 25, 
26, 27, 28 and 29.sup.1 . . . 29.sup.n. 
Upon use, saline solution is pumped from reservoir 18 through the system 
into the waste bottle (valves 24, 27 and 28 open). Then N.sub.2 flush 
(valves 25 and 28 open), followed by reverse rotation of pump (see above). 
Thereupon the generator is eluted by pumping saline solution through the 
generator into the eluate reservoir 20 (valves 24 and 26 open). Again 
N.sub.2 flush and reversed rotation of pump. Then a predetermined quantity 
of the eluate (valves 27 and 29.sup.1 open), if desired together with a 
predetermined quantity of saline solution (valve 24 also open), is pumped 
into the delivery station and is directly dispensed in kit vial k.sub.1. 
After N.sub.2 flush and reversed rotation of pump this discharge-dispense 
operation can be repeated with sequentially opened valves 29.sup.2 . . . 
29.sup.n, depleting into kit vials k.sub.2 . . . k.sub.n. It will be 
obvious from the description hereinbefore, that the quantities and 
radioactivities of the supplied liquids are continuously monitored and 
that all conveying operations are program-controlled.