Leaflet GALLIAPHARM 1.85 GBq radionuclide generator

Elution of the radionuclide generator must be performed in premises complying with the nationalregulations concerning the safety of use of radioactive products.

The general handling, the attachment of tubing, the exchange of the sterile ultrapure 0.1 mol/lhydrochloric acid container, the elution of the generator and other activities potentially exposing thegenerator to the environment should be undertaken using aseptic techniques in an appropriate cleanenvironment according to current national legislation.

Unpacking of the radionuclide generator:

1. Check outer shipping package for shipping damage. If damaged, perform radiation wipe surveyof the damaged area. If counts exceed 40 counts per second per 100 cm2, notify your Radiation

Safety Officer.

2. Cut security seal on top of shipping package. Remove the inner foam support from the shippingpackage. Separate the foam elements carefully.

3. Carefully remove radionuclide generator.

CAUTION: Drop hazard: The radionuclide generator weighs approx. 14 kg. Handle with careto avoid potential injuries. If radionuclide generator is dropped or if shipping damage extendsinto the shipping package, check for leaks and perform a wipe survey of the radionuclidegenerator. Also check for internal damage by slowly tilting the radionuclide generator 90°.

Listen for broken/loose parts.

4. Perform wipe survey of shipping package inserts and radionuclide generator outer surface. Ifwipes exceed 40 counts per second per 100 cm2, notify your Radiation Safety Officer.

5. Check sealed inlet and outlet ports for damage. Do not remove the port plugs before the elutionlines are prepared and ready for installation.

Optimal positioning:

1. When installing the radionuclide generator in its final position, i.e., with a synthesis device orfor manual elutions, it is recommended to keep the outlet line as short as possible as the lengthof this tubing may influence the yield in the receiving/reaction vial. For this reason, theradionuclide generator is supplied with three different lengths of tubing to choose theappropriate length.

2. Local auxiliary shielding is recommended when positioning the radionuclide generator.

Please note: Moving the radionuclide generator after installation in its final position should be avoided.

Assembly of the radionuclide generator:

Accessories supplied with the radionuclide generator (minimum amounts):

1. 1 x PP - container with the eluent, 250 ml sterile ultrapure 0.1 mol/l hydrochloric acid(including a separate hanger for PP-bottles; PP = Polypropylene)2. 1 x Vented spike (ABS = Acrylonitrile Butadiene Styrene/PE = Polyethylene).3. 2 x Adapter 1/16' to male LUER (PEEK)4. 2 x Tubing 60 cm (PEEK)5. 1 x Tubing 40 cm (PEEK)6. 1 x Tubing 20 cm (PEEK)7. 3 x Fingertight fitting 1/16' 10-32 (PEEK)8. 1 x Fingertight fitting 1/16' M6 (PEEK)9. 1 x Stopcock manifold (TPX = Polymethylpentene/HDPE = High Density

Polyethylene)10. 1 x Male LUER union (PP)

Assemble the radionuclide generator in an appropriately clean environment. Aseptic workingtechnique must be maintained during the whole assembly process. Wear gloves during preparation andconnecting of the lines to the radionuclide generator and to the eluent container. This is critical for themaintenance of sterility.

Picture of assembled elution accessories before connection to the radionuclide generator (Theindicated identification numbers of accessories are as presented in the list above. They are also useda ccordingly in the pictures and assembly instructions following below.):

1. Assembling the inlet line:

Please note: the inlet port has a customised thread toavoid misconnection. Only the special fingertightfitting 1/16' M6 will fit into this port. Forassembling the inlet line, connect the vented spike(2) to one end of the stopcock manifold (9) using themale LUER union (10) [I]. On the other end of thestopcock manifold (9) connect the adapter 1/16' tomale LUER (3) [II]. Attach one of the 60 cm long

PEEK tubing (4) with a 1/16' 10-32 fingertightfitting (7) [III]. Put the special 1/16' M6 fingertightfitting (8) on the other end of the line, but do notconnect yet [IV].

2. Assembling the outlet line:

For the outlet line, choose the appropriate length oftubing (20 cm, 40 cm, or 60 cm) based on your localsetting. Use the shortest line possible. Attach thechosen PEEK line (4,5 or 6) to the second adapter1/16' to male LUER (3) using a 1/16' 10-32fingertight fitting (7) [V]. Put the third 1/16” 10-32fingertight fitting (7) on the other end of theprepared outlet line, but do not connect yet [VI].3. Connecting the hydrochloric acid containerto the inlet line:

Hang the PP - container with the 250 ml sterileultrapure 0.1 mol/l hydrochloric acid solution closeto the inlet port above the radionuclide generator.

The valves of the stopcock manifold have a T-typeflow pattern with three openings inside - one in eachdirection of the external prongs. Turn the valves atthe stopcock manifold in the appropriate direction(3-6-9 clock position ┳) so that no liquid can enterthrough the spike [VII]. Remove the lid of thevented spike and push the vented spike into the PP -container connection [VIII].

Now the air must be removed from the stopcockmanifold and the attached inlet line. Be aware, thathydrochloric acid will thereby flow through andmay drip out of the line and the side ports. Beprepared to remove the drops immediately.

To remove the air, start by turning both valves of thestopcock manifold as shown in the picture [IX] (theprongs of both valves should be in the 6-9-12 clockposition ┫). This will fill the inlet line with liquidand push the air out of it. Then turn the upper valveinto the 9-12-3 clock position ┻ and remove the capof the upper side port to remove the air [X].

Afterwards, close the upper side port again with thecap. Now turn the upper valve back into the 6-9-12clock position ┫. Turn the lower valve into the 9-12-3 clock position ┻ and remove the cap of thelower side port to remove the air [XI]. Close thelower side port again with the cap. Finally, place theupper valve into the 3-6-9 clock position ┳ to stopflow of the liquid from the hydrochloric acidcontainer [XII].

4. Connecting the inlet line to the port of theradionuclide generator:

Remove the plug from the inlet port of theradionuclide generator [XIII]. To connect preparedand filled inlet line using the 1/16' M6 fingertightfitting, push the line into the inlet port [XIV] andscrew in the fingertight fitting [XV]. Avoid hardbending or pinching of the line.

5. Connecting the outlet line to the port of theradionuclide generator:

Remove plug from the outlet port of the radionuclidegenerator [XVI]. To connect prepared outlet lineusing the 1/16' 10-32 fingertight fitting, push theline into the outlet port [XVII] and screw in thefingertight fitting [XVIII]. Avoid hard bending orpinching of the line.

The radionuclide generator is now ready for the first elution:

Please note: The radionuclide generator is designed not to drain itself, when no lines are connectedto the inlet and outlet ports, but it is not recommended to leave the ports open at any time.

When the container with the sterile ultrapure 0.1 mol/l hydrochloric acid is connected and the fluidpath is open, the radionuclide generator will be eluted by gravity. Therefore, it is necessary to keepthe inlet and outlet lines as well as the positions of the stopcock valves under control.

First manual elution:

1. Prepare additional necessary materials:

− Personal protective equipment: elutions should be performed while wearing eye and handprotection, and appropriate laboratory cloth.

− Sterile syringe with 10 ml volume (avoid syringes with rubber plunger, preferably use two-piece syringes).

− Shielded receiving vial or vessel with 10 ml or larger volume. Avoid uncoated stoppers asthey may contain considerable amounts of zinc that is extracted by the acidic eluate.

2. Attach the syringe to the upper side port of thestopcock manifold and fill with 10 ml ofsterile ultrapure 0.1 mol/l hydrochloric acidfrom the PP - container by turning the valveinto the shown position, then moving theplunger of the syringe in the indicateddirection while avoiding any air inside thesyringe [XIX].

3. Connect the shielded receiving vessel to the outlet line using the appropriate connector. Thevessel must have sufficient capacity to accept the eluate volume. Avoid using metal syringeneedles for connection.

4. Turn both valves of stopcock manifoldtowards the inlet port of the radionuclidegenerator. Push the 10 ml sterile ultrapure0.1 mol/l hydrochloric acid at a flow rate notgreater than 2 ml/minute [XX]. Eluting at afaster flow rate may reduce the shelf-life ofthe radionuclide generator. Five millilitres ofeluent will fully elute the radionuclidegenerator, but for the first elution it is recommended to use 10 ml. If high resistance isencountered, do not force solution into radionuclide generator. If a peristaltic pump is used forelution, it should be set to a flow rate of not more than 2 ml/minute. The user should also verifythat eluent is flowing without unusual resistance. If high resistance is noticed, discontinue elution.

CAUTION:

Be sure to introduce eluent through the inlet port; do not elute the radionuclide generator inreverse direction.

Elution efficiency (68Ga yield) may be reduced if air is introduced into the radionuclidegenerator column.

5. Collect eluate in shielded receiving vessel and measure solution with a calibrated dose calibratorto determine the yield. If less than 5 ml of eluate have been collected, measurement may notrepresent the total potential yield of radionuclide generator. Please decay correct the measuredactivity to the starting time of the elution. For optimal yield of the radionuclide generator in itsfinal position it is recommended to determine the elution peak by collecting small fractions of0.5 ml.

6. The first eluate should be discarded due to the potential 68Ge breakthrough in this eluate.

It is recommended to test the eluate for 68Ge breakthrough after the first elutions by comparing theactivity level of the 68Ga and the 68Ge. For further details please refer to Ph. Eur. monograph 2464.

Routine elution:

CAUTION:

Free 68Ge ions can accumulate in the column over time. If the radionuclide generator has not beenused for a period of 96 hours or more, the column should be pre-eluted once, at least 7 hours prior toeluting for radiolabelling. If the radiolabelling procedure does not require maximum achievable eluateactivity, the time between the pre-elution and the elution for radiolabelling can be reduced (see alsotable 6 and calculation example below it). The pre-elution should be done using 10 ml of sterileultrapure 0.1 mol/l hydrochloric acid.

1. Repeat the steps of the first elution but use only 5 ml eluent for the routine elution. Theradionuclide generator is designed to elute all of the available 68Ga activity in a volume of 5 ml.

2. The eluate is a clear, sterile, and colourless gallium (68Ga) chloride solution, with a pH between0.5 and 2.0 and a radiochemical purity greater than 95 %. Check the clarity of the eluate beforeuse and discard it if the solution is not clear.

3. It is recommended to test the eluate for 68Ge breakthrough during routine elutions by comparingthe activity level of the 68Ga and the 68Ge. For further details please refer to Ph. Eur. monograph2464.

CAUTION:

If fluid leaks are observed at any time, immediately stop eluting and attempt to contain the leakingfluid.

The radionuclide generator is supplied with 250 ml of sterile ultrapure 0.1 mol/l hydrochloric acid.

This amount is usually sufficient for at least 40 elutions. The radionuclide generator should only beeluted with sterile ultrapure 0.1 mol/l hydrochloric acid supplied by the marketing authorisationholder. Additional containers may be purchased as consumables from the marketing authorisationholder only.

Exchange of sterile ultrapure 0.1 mol/l hydrochloric acid container:

CAUTION:

Aseptic technique is critical for maintenance of sterility and must be used during the exchangeprocedure.

1. When the sterile ultrapure 0.1 mol/l hydrochloric acid is almost consumed, the empty containercan be replaced by a new sterile ultrapure 0.1 mol/l hydrochloric acid container.

CAUTION:

No air should enter the radionuclide generator.

Before disconnecting the empty container, close allvalves at the stopcock manifold and cap the sideports so that no air can enter into the manifold andspike [XXI]. Disconnect the container from thevented spike [XXII]. It is recommended to replacethe vented spike with the new sterile vented spikesupplied with each new sterile ultrapure 0.1 mol/lhydrochloric acid container.

2. Hang the new container with the 250 ml sterile ultrapure 0.1 mol/l hydrochloric acid close to theinlet port above the radionuclide generator.

3. Push the connected vented spike into the container stopper; carefully check for air bubbles andslowly remove all air from the stopcock manifold using the valves. It is not necessary to detachthe attached inlet line from the radionuclide generator or from the stopcock manifold. Enteringof air into the radionuclide generator should be avoided.

4. When stopcock manifold is filled, close valves to stop flow. The radionuclide generator is nowready for elution again.

Radionuclide generator elution yield:

The activity stated on the label of the radionuclide generator is expressed in 68Ge available at thecalibration date (12:00 CET). The available 68Ga activity depends on the 68Ge activity at the time ofelution and the elapsed time since the previous elution.

A radionuclide generator in full equilibrium yields more than 60 % of 68Ga using an elution volume of5 ml sterile ultrapure 0.1 mol/l hydrochloric acid.

The output will decrease with decay of the parent nuclide 68Ge over time. For example, after 9 months'decay (39 weeks), the 68Ge will be reduced by 50 % (see table 5). To calculate the current 68Geactivity, multiply the 68Ge activity at calibration date with the respective decay factor of thecorresponding elapsed time in weeks.

Table 5: Decay Chart for 68Ge

Elapsed Time Decay Factor Elapsed Time Decay Factorin weeks in weeks1 0.98 40 0.492 0.96 41 0.483 0.95 42 0.474 0.93 43 0.465 0.91 44 0.456 0.90 45 0.457 0.88 46 0.448 0.87 47 0.439 0.85 48 0.4210 0.84 49 0.4211 0.82 50 0.4112 0.81 51 0.4013 0.79 52 0.3914 0.78 53 0.3915 0.76 54 0.3816 0.75 55 0.3717 0.74 56 0.3718 0.72 57 0.3619 0.71 58 0.3520 0.70 59 0.3521 0.69 60 0.3422 0.67 61 0.3423 0.66 62 0.3324 0.65 63 0.3225 0.64 64 0.3226 0.63 65 0.3127 0.62 66 0.3128 0.61 67 0.3029 0.59 68 0.3030 0.58 69 0.2931 0.57 70 0.2932 0.56 71 0.2833 0.55 72 0.2834 0.54 73 0.2735 0.53 74 0.2736 0.52 75 0.2637 0.52 76 0.2638 0.51 77 0.2539 0.50 78 0.25

After elution, the 68Ga will be built up by the continuous decay of the parent 68Ge. The radionuclidegenerator requires at least 7 hours to achieve almost full yield after being eluted, but in practice it isalso possible to elute the radionuclide generator earlier, depending on its strength and the activityrequired for radiolabelling. Table 6 shows the build-up factor of 68Ga activity over time, up to410 minutes after an elution.

Table 6: Build-up factors of 68Ga

Elapsed Time Build-Up Elapsed Time Build-Upin minutes Factor in minutes Factor0 0.00 210 0.8810 0.10 220 0.8920 0.19 230 0.9130 0.26 240 0.9140 0.34 250 0.9250 0.40 260 0.9360 0.46 270 0.9470 0.51 280 0.9480 0.56 290 0.9590 0.60 300 0.95100 0.64 310 0.96110 0.68 320 0.96120 0.71 330 0.97130 0.74 340 0.97140 0.76 350 0.97150 0.78 360 0.97160 0.81 370 0.98170 0.82 380 0.98180 0.84 390 0.98190 0.86 400 0.98200 0.87 410 0.98

Calculation examples

A 1.85 GBq radionuclide generator is 12 weeks old. According to table 5, the activity of 68Ge on thecolumn can be calculated as follows:

1.85 GBq × 0.81 = 1.50 GBq

In full equilibrium, the activity of 68Ga on the column is also 1.50 GBq.

The radionuclide generator is eluted and the collected 68Ga activity is 1.05 GBq which corresponds toa yield of 70 %.

The same radionuclide generator is eluted 4 hours later. The 7 hours needed to reach the 68Ge/68Ga-equilibrium have not elapsed yet. The 68Ga activity built up on the column in 4 hours (240 minutes)post-elution can be calculated according to table 6 as follows:

1.50 GBq × 0.91 = 1.37 GBq

With a typical yield of 70 % 68Ga, the collected activity would then be:

1.37 GBq × 0.70 = 1.00 GBq

Note:

The activity of 68Ga in the eluate can be measured to check the quality with regard to identity andcontent. The activity should be measured immediately after elution but may also be measured up to5 half-life periods after elution.

Due to the short half-time of 68Ga (67.71 minutes), the elapsed time between the elution and themeasurement of the activity has to be decay-corrected to determine the actual yield at the elution timewith the decay chart of 68Ga, table 7.

Calculation Example

A new 1.85 GBq radionuclide generator is eluted. The activity of 68Ga measured 10 minutes after theelution was 1.17 GBq.

The yield at the time of the elution can be obtained by dividing the measured activity by thecorresponding decay factor of the elapsed time stated in table 7:1.17 GBq/0.90 = 1.30 GBq

This corresponds to a yield of 68Ga of 70 % at the time of the elution:1.30 GBq/1.85 GBq × 100 % = 70 %

Table 7: Decay chart of 68Ga

Elapsed Time Decay Factor Elapsed Time Decay Factorin minutes in minutes1 0.99 35 0.702 0.98 36 0.693 0.97 37 0.694 0.96 38 0.685 0.95 39 0.676 0.94 40 0.677 0.93 41 0.668 0.92 42 0.659 0.91 43 0.6510 0.90 44 0.6411 0.89 45 0.6312 0.89 46 0.6313 0.88 47 0.6214 0.87 48 0.6115 0.87 49 0.6116 0.85 50 0.6017 0.84 51 0.6018 0.83 52 0.5919 0.82 53 0.5820 0.82 54 0.5821 0.82 55 0.5722 0.80 56 0.5723 0.79 57 0.5624 0.78 58 0.5525 0.78 59 0.5526 0.77 60 0.5427 0.76 61 0.5428 0.75 62 0.5329 0.74 63 0.5330 0.74 64 0.5231 0.73 65 0.5232 0.72 66 0.5133 0.71 67 0.5134 0.71 68 0.50

Quality control

If possible, clarity of the solution, pH and the radioactivity should be checked before radiolabelling.

68Ge breakthrough

A small amount of 68Ge is washed from the radionuclide generator column with each elution. 68Gebreakthrough is expressed as a percentage of total 68Ga activity eluted from the column, corrected fordecay, and does not exceed 0.001 % of the eluted 68Ga activity. 68Ge breakthrough can, however,increase above 0.001 % if the radionuclide generator is not eluted for several days. Therefore, if theradionuclide generator has not been eluted for 96 hours or more, it should be pre-eluted with 10 ml ofsterile ultrapure 0.1 mol/l hydrochloric acid at least 7 hours prior to the intended use (the time betweenthe pre-elution and the elution for radiolabelling can be reduced if the intended radiolabellingprocedure does not require maximum achievable eluate activity). When this instruction is followed,the 68Ge breakthrough should constantly stay below 0.001 % in eluates obtained for radiolabelling. Fortesting the 68Ge breakthrough, the activity levels of 68Ga and 68Ge in the eluate should be compared.

For further details please refer to Ph. Eur. monograph 2464.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Detailed information on this medicinal product available on the website of the European Medicines

Agency http://www.ema.europa.eu.