An automated radiopharmaceutical dispenser

An automated radiopharmaceutical dispenser

Appl. Radiat. Isot. Vol. 48, No. 3, pp. 345-348, 1997 ~ Pergamon PII: S0969-8043(96)00215-1 Publishedby ElsevierScienceLtd Printed in Great Britai...

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Appl. Radiat. Isot. Vol. 48, No. 3, pp. 345-348, 1997

~

Pergamon

PII: S0969-8043(96)00215-1

Publishedby ElsevierScienceLtd Printed in Great Britain.All rights reserved o969-8o43/97 $17.oo+ 0.oo

An Automated Radiopharmaceutical Dispenser P. S. P L A S C J A K * , K . K I M , W . M E Y E R J R , J. D I V E L , M. D E R a n d W . C. E C K E L M A N PET Department, National Institutes of Health, Bethesda, MD 20892, U.S.A. (Received 24 January 1996; in revised form 18 June 1996)

An automated radiopharmaceutical dispenser, that offers several advantages over manual procedures, has been developed. It employs a personal computer interfaced to a precision syringe drive module, a dose calibrator, and a printer. The operating program provides menu-selection operation and documentation of procedures and individual doses delivered. All materials in contact with the radiopharmaceutical are sterile and disposable. A novel transport safe is employed to further reduce radiation exposure. Published by Elsevier Science Ltd. All rights reserved

Introduction The radiopharmacy in the positron emission tomography (PET) department at the National Institutes of Health (NIH) dispenses multiple doses of 2-[F-18]-fiuoro-2-deoxyglucose (FDG) from a single product vial over a 9 h period. The doses must be precalibrated to deliver the requested amount of F D G (usually 185 or 370 MBq [5 or 10 mCi]) at the time of injection. The dose is infused into the patient over several minutes in a volume of 9 mL. The manual dispensing procedure involved withdrawing the individual doses from a vial that initially contained as much as 13 GBq (350 mCi) of F D G immediately after being released by quality control. The need to swipe and puncture the vial septum, measure the volume containing the appropriate dose of F D G , and dilute to 9 mL, led to potentially high radiation exposure for the radiopharmacist. To reduce this radiation exposure, an automated dispenser was developed. The key design criteria were: a simple setup and operation, accurate dispensing of 185-370 MBq (5-10 mCi) doses of F D G in a volume of 9 mL, maintaining purity, sterility and apyrogenicity of the individual doses, and computer control of the process with thorough process and dose documentation.

Materials and Methods The radiopharmaceutical dispenser consists of a personal computer which communicates with a printer (model LJ 5P, Hewlett-Packard) and, via *To whom all correspondence should be addressed.

RS-232 ports, with a dose calibrator (model CRC-15R, Capintec; Pittsburgh, Pa) and a modified precision syringe drive unit (model PSD/2, Hamilton; Reno, NV). The dispensing unit (Fig. 1) is located in a laminar flow hood with the computer, printer and dose calibrator outside. A 2.5 cm thick lead shield surrounds the syringe drive unit (C) and product syringe (L). The dose syringe panel (J) is located on the outside of the shield. A disposable, sterile, custom tube set (Fig. 2 and Fig. 1, B; no. IV-2035-1), Braun; Bethlehem, Pa) connects the all-plastic disposable 20 mL sterile syringe (Fig. 1, L ; HSW Norin-Ject, Baxter; Columbia, Maryland) to the 12 mL dose syringe (F) and the saline supply (A). Radiation exposure was further reduced by using the transport safe (Fig. 3) to transport the product vial from the radiochemistry area to the radiopharmacy, assay the product vial in the dose calibrator and facilitate product transfer into the dispenser without directly exposing the pharmacist to as much as 13 GBq (350 mCi) of radioactivity. Dispenser

A Texas Instruments TravelMate 4000E (486DX2/ 50) laptop computer was used for the prototype development, because it supported the program development environment (Microsoft Basic, Professional Development System, version 7.1). The executable dispenser operating program can be accommodated by any IBM/AT-compatible personal computer with two RS-232 ports and a printer port. The precision syringe drive unit (Fig. 1, C) accepts ASCII commands through a RS-232 port to control an integral valve positioner, syringe drive and digital I/O port.

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Adapters (K and N) were fabricated which allow the unit to accept the product syringe (L) and a three-way stopcock valve (M). The product syringe is held securely in place by locating the flange of the syringe body and the plunger in milled slots on the syringe drive adapters (K) and locking with thumbscrews. The stopcock handle is located in a milled sl0t in the valve positioned adapter (N). Two stopcock positions permit the delivery line to connect to either the product syringe (L) or the saline supply (A). A digital output on the syringe drive unit is used to control a solenoid valve (I) through a solid-state relay. This valve controls a vacuum actuator (H) constructed from a 20 mL syringe which pulls the dose syringe plunger to a stop to dilute the delivered dose to 9 mL.

Val ad~ Sto

Transport safe Design considerations for the transport safe (Fig. 3) included: minimizing radiation exposure, safe and easy handling, and convenient access to the product vial septum during product transfer operations. The transport safe is 54 cm high, 12 cm in diameter and weighs 10 kg. Measured exposure rates 20 cm from the surface in all directions except below the safe were less than 3.87 C k g - ~ h - ~ (15 mR h - ~) when the safe contained 9.25 GBq (250 mCi) of fluorine-18. 25.8 C kg-~ h-~ (100 mR h - l ) was measured 20 cm below the safe. When closed for transport, it offers a comfortable handle height and low center of gravity. The handle (A) is connected to the Lexan (DuPont, Inc.) vial elevator (F) by stainless steel rods which pass through bearings in the upper shield (D). The lower shield (G) is removed by rotating the elevator handle (A) counter-clockwise when the unit is resting on the floor and lifting the upper shield assembly away. The product vial (E) is loaded into the safe by resting the upper shield on a support with an open center section and lowering the vial elevator (F) to expose the vial holder. The lead plug (B) is placed over the septum access port (C). The product vial is placed in the elevator and lifted into the upper shield when the handle is raised~ The lower shield is reattached by lowering the assembly into the lower shield and rotating the handle clockwise. The safe assembly can be lifted by the elevator handle and transported comfortably and securely. Th E product vial is assayed by detaching the lower shield and placing the upper shield over the ion chamber well with the liner removed. The handle is pushed down to locate the vial at the bottom of the well. After the assay, the handle is raised and the lower shield reattached. The assembly is then transported to the laminar flow hood for product transfer from the product vial into the product syringe in the dispenser. Raising the lead plug (B) exposes the product vial septum for alcohol swiping and needle insertion.

20~ Pro Syr Syr Act, Ad~ Do., MoL

Lea Line

Fig. 1. Layout of assembled dispensing unit

Dispenser operation The dispenser is prepared by installing the tube set (Fig. 1, B) and product syringe (L). The saline bag (A) is attached to the tube set and located above the

Flow Chamber

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I.V. Tubing ) Roller Clamp

Backcheck Valve

Smallbore Tubing (30cm)

Female Luer-Lock

Three-way Stopcock ( no stops )

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NO. IV-2035-D Sterile-disposable Tube Set, Braun Medical, Inc.

Fig. 2. Custom fabricated sterile-disposable tube set. Available from B. Braun Medical, Inc., Bethlehem, PA 18018.

Automated radiopharmaceutical dispenser

Elevator die (A) Lead Plug(B)

SeptumAccess Port(C) Upper

Shield (D)

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Product

! Vial(E) ~

'

~

Vial Elevator(F)

Lower

Shield (G)

Fig. 3. Radiopharmaceutical transport safe.

dispenser. The syringe drive unit assembly (C) is placed in the lead shield and the delivery line (D) is attached to a 18 ga. × 3 1/2 in spinal needle. The computer program is started and the syringe drive, dose calibrator interface and printer are initialized and tested by the computer. Error messages alert the operator to system problems and suggest solutions. Upon arrival of the radiopharmaceutical, the operator selects the transfer process from the displayed menu. The computer instructs the pharmacist to manually remove a 1 mL aliquot from the product vial for quality control testing and assay the remainder. The activity value and time are automatically stored in computer memory and the operator is then instructed to prepare for transfer of the product into the dispenser. After an alcohol swipe, the spinal needle on the delivery line is inserted into the 20 mL product vial through the septum access port in the transfer safe (Fig. 3, C). A filtered vent needle is installed and the operator advances the computer program. Under computer control, the radiopharmaceutical is drawn into the product syringe (Fig. 1, L). The product syringe is purged of bubbles by pushing liquid back into the product vial and redrawing. The operator observes the delivery line and controls the product syringe from the computer keyboard until bubble-free liquid is seen in the delivery line (D). The computer then commands the valve positioner (N) on the syringe drive unit to rotate (connecting the saline supply to the delivery line) and the operator is instructed to purge bubbles from the saline line. This rinses remaining activity in the delivery line into the empty product vial. The operator reassays the product vial and the computer calculates, logs, and displays relevant data from the transfer. The spinal

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needle is replaced by a 12 mL dose syringe (F) and the delivery line (D) is then damped to the hinged plate (E) on the dose syringe panel (J). The plunger on the dose syringe is then pressed into the sliding coupler (G). The computer displays a menu that permits dose dispensing or printing of logged data. This screen also displays information about the activity and volume available in the product syringe calculated from volume data received f r o m the syringe module and the decay-corrected activity difference of the assays made during transfer: To dispense a dose, the operator selects the menu item and enters patient data, protocol information and the desired activity at the time o f patient injection. The computer calculates the volume required from the product syringe, commands the valve positioner to rotate (connecting the product syringe .to the dose syringe) and commands the syringe drive t o dispense the calculated volume. After the volume is transferred, the valve positioner is returned to the position connecting the saline supply to the dose syringe. The computer then commands the solenoid valve (I) to open and the dose syringe plunger is pulled to a stop by the actuator filling the syringe to 9 mL with saline. The dose syringe is manually removed, assayed, and replaced by a new syringe. The computer calculates and logs dose information and prints a form which accompanies the dose to the patient. The volume and activity remaining in the product syringe is calculated and displayed by the computer. The dispensing procedure can be repeated as required or until the activity remaining in the product syringe is exhausted. If the dose requested exceeds that remaining in the dispenser, the operator is offered the option to take all remaining activity. A menu option is available to print an operation summary from logged data for quality control and radiopharmacy printed archives. Quality control Product radiochemical stability was measured by delivering samples for testing at approximately 1 h intervals for 9 h. 11.8 GBq (320 mCi) of F D G in 16 mL of saline and potassium phosphate buffer was transferred into the dispenser and samples delivered from the dispenser were tested by TLC [silica gel 60 HPTLC in acetonitrile/water (95:5)] (Adams et al., 1995). The radiochemical purity decreased less than 2% from the starting purity of 97.8%. Pyrogenicity of delivered samples from each F D G batch is routinely tested by the Limulus Arnebocyte Lysate test (LAL, Pyrotel; Falmouth, Mass.). All 15 batches tested for pyrogens showed less than 4.0 EU m L - 1. Sterility samples were dispensed from each product batch at the end of the work day and sent to the Food and Drug Administration Center for Biologics Evaluation and Research and tested by the United States Pharmacopoeia (USP XXII/74 Sterility Tests) method of direct inoculation on fluid thioglycollate

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medium and soybean-casein digest medium. Ten samples completed testing and all proved sterile.

Results and Discussion We have developed an automated device for dispensing F D G under computer control. Setup and use of the device was quickly learned. Modifications to the operating program were easily made during device testing in response to the desires of the radiopharmacists and to permit device tuning. Decay calculations are made by the computer and doses are delivered calibrated for their intended injection time. Dose delivery and equipment operation documentation is completely automated: computer files are maintained that document product transfer into the dispenser and dispensing operations, and information on each delivered dose is appended to an archive file which includes associated dispenser parameters. Performance parameters and accuracy of operations are easily determined. No data are available to quantify personnel exposure reduction due to use of this device, but exposure rates are much reduced compared to when manual methods were previously used.

Dispenser performance

Based on the assays performed during transfer of the F D G from the product vial to the dispensing syringe (about 17 mL), 92.8% of the radioactivity (standard deviation --- 2.3%, n = 15) was successfully transferred. Dispensed doses have averaged 101.58% (s.d. = 1.22%, n = 59) of the desired activity. The repeatability of the dose calibrator is specified to be + 1% (Capintec, Inc., 1988). No equipment failures have been experienced and all dispensed doses have been determined suitable for use. Acknowledgements--The authors thank R. K. Leedham for his many helpful suggestions during the development of this device.

References Adams H. R., Channing M. A., Divel J. E., Dunn B. B., Kiesewetter D. O., Plascjak P., Regdos S. L., Simpson N. R. and Eckelman W. C. (1995) Chemists' View oflmaging Centers (Emran A. M., Ed.), p. 175. Plenum Press, New York. Capintec Inc. (1988) Radioisotope Calibrator Owner's Manual for Models CRC-7, CRC-12 and CRC-120, Rev. F. Capintec Inc., Pittsburg, Pa.