Preparation and Dispensing Problems Associated with Technetium Tc-99M Radiopharmaceuticals
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THE UNIVERSITY OF NEW MEXICO HEALTH SCIENCES CENTER COLLEGE OF PHARMACY ALBUQUERQUE, NEW MEXICO Correspondence Continuing Education Courses for Nuclear Pharmacists and Nuclear Medicine Professionals VOLUME 11, LESSON 1 Preparation and Dispensing Problems Associated with Technetium Tc-99m Radiopharmaceuticals By James A. Ponto, MS, RPh, BCNP University of Iowa Hospitals and Clinics, and College of Pharmacy Iowa City, IA The University of New Mexico Health Sciences Center College of Pharmacy is accredited by the American Council on Pharmaceutical Education as a provider of continuing pharmaceutical education. Program No. 039- 000-04-003-H04. Expires May 25, 2007. 2.5 Contact Hours of .25 CEUs. Preparation and Dispensing Problems Associated with Technetium Tc-99m Radiopharmaceuticals By: James A. Ponto Coordinating Editor and Director of Pharmacy Continuing Education William B. Hladik III, MS, RPh College of Pharmacy University of New Mexico Health Sciences Center Managing Editor Julliana Newman, ELS Wellman Publishing, Inc. Albuquerque, New Mexico Editorial Board George H. Hinkle, MS, RPh, BCNP William B. Hladik III, MS, RPh David Laven, NPh, CRPh, FASHP, FAPhA Jeffrey P. Norenberg, MS, PharmD, BCNP, FASHP Neil A. Petry, RPh, MS, BCNP, FAPhA Timothy M. Quinton, PharmD, MS, RPh, BCNP Guest Reviewer Joseph Hung, PhD Director, Nuclear Pharmacy Laboratories and Positron Emission Tomography (PET) Radiochemistry Facility Mayo Clinic 200 First St. S.W. Rochester, MN 55905 While the advice and information in this publication are believed to be true and accurate at press time, the author(s), editors, or the publisher cannot accept any legal responsibility for any errors or omissions that may be made. The publisher makes no war- ranty, express or implied, with respect to the material container herein. Copyright 2004 University of New Mexico Health Sciences Center Pharmacy Continuing Education Albuquerque, New Mexico PREPARATION AND DISPENSING PROBLEMS ASSOCIATED WITH TECHNETIUM TC-99M RADIOPHARMACEUTICALS STATEMENT OF OBJECTIVES The purpose of this lesson is to increase the reader’s knowledge and understanding of problems associated with the preparation and dispensing of Tc-99m radiopharmaceuticals and the corre- sponding effects/manifestations of these problems. Upon completion of this lesson, the reader should be able to: 1. Describe common Tc-99m radiochemical impurities and their clinical manifestations. 2. Describe preparation problems associated with using Tc-99m generator eluates. 3. Describe other common problems encountered when radiolabeling Tc-99m kits. 4. Discuss the incidence of preparation problems associated with Tc-99m radiopharmaceuti- cals. 5. Describe common problems associated with dispensing of Tc-99m radiopharmaceuticals. COURSE OUTLINE I. Filtration J. Specific Activity/Mass I. INTRODUCTION K. Summary of Preparation Prob- lems II. COMMON RADIOCHEMICAL IMPURITIES AND THEIR V. INCIDENCE OF PREPARATION CLINICAL MANIFESTATIONS PROBLEMS III. PROBLEMS ASSOCIATED VI. DISPENSING PROBLEMS WITH Tc-99m GENERATOR A. Decomposition During Storage ELUATES B. Agitation A. Inadequate Stannous:Technetium C. Sedimentation of Particles Molar Ratio D. Adsorption to Container Walls B. Radiolytic Effects E. Interaction with Container Com- C. Compromised Integrity ponents D. Recommendations F. Interaction with Antiseptics G. Summary of Dispensing Prob- IV. OTHER COMMON PROBLEMS lems INVOLVED IN RADIOLABEL- ING KITS VII. CONCLUSION A. Improper Heating B. Improper Mixing Order VIII. REFERENCES C. Reagent Concentration D. Incubation/Time Delays IX. APPENDIX 1 E. Commercial Source F. Bacteriostatic Preservatives X. APPENDIX 2 G. Other Diluents H. Aluminum XI. QUESTIONS 1 PREPARATION AND DISPENSING COMMON RADIOCHEMICAL IMPU- PROBLEMS ASSOCIATED WITH RITIES AND THEIR CLINICAL TECHNETIUM TC-99M RADIO- MANIFESTATIONS PHARMACEUTICALS In addition to the desired product, Tc- 99m radiopharmaceuticals may also contain By various radiochemical impurities. Each of James A. Ponto, MS, RPh, BCNP these impurities, being a different chemical University of Iowa Hospitals and Clinics, species, exhibits a biodistribution in the body and College of Pharmacy different from the desired radiopharmaceuti- Iowa City, IA cal with resultant unintended localization in other various organs and tissues. Hence, de- pending on the specific parameters of the im- INTRODUCTION aging procedure, the radiochemical impurity In contrast to conventional drugs, Tc-99m may interfere with diagnostic interpretation labeled radiopharmaceuticals have several of the images by masking disease, mimicking unique characteristics that are potentially disease, or otherwise resulting in non- problematic in their preparation and dispens- diagnostic image quality. Also, radiochemi- ing: cal impurities may impart unnecessary radia- 1. Their preparation involves chemical re- tion exposure to non-target organ(s). actions that may produce undesired ra- The predominant radiochemical impurity diochemical impurities; associated with most Tc-99m radiopharma- 2. Their emitted radiation, especially at ceuticals is free, unlabeled Tc-99m in the high intensities, may produce radiolytic chemical form of pertechnetate ion (i.e., - effects that can result in undesired impu- TcO4 ). Pertechnetate distributes throughout rities; the vasculature and interstitial fluid, and con- 3. Their chemical properties, especially in centrates primarily in the stomach, intestinal combination with their small mass quan- tract, urinary tract, thyroid gland, and sali- tities, may result in undesired adsorption vary glands. A second radiochemical impu- to container components or interaction rity associated with some Tc-99m radio- with trace contaminants leached there- pharmaceuticals is insoluble Tc-99m in the from. chemical form of technetium hydroxides or These problems may subsequently result technetium labeled stannous hydroxide (also in unexpected alterations in biodistribution referred to as hydrolyzed-reduced techne- and/or inadequate localization in organs of tium). These species are in the physical form interest, and thereby interfere with diagnostic of colloid particles which are phagocytized interpretation. by cells of the reticuloendothelial system lo- The purpose of this lesson is to briefly cated primarily in the liver, spleen, and mar- describe many of these common problems, row. A third radiochemical impurity associ- including the underlying causes and possible ated with a few Tc-99m radiopharmaceuticals methods of minimization/avoidance. Al- is large aggregates of particles. Particles lar- though many of these problems have been ger than 10 microns become physically 1-4 described in past reviews on this topic, this lodged in the first capillary bed they encoun- lesson aspires to update and reorganize such ter; i.e., following intravenous injection, they information in order to enhance understand- lodge in the pulmonary capillaries. ing of the subject and to provide a ready ref- A variety of other radiochemical impuri- erence. ties may also be formed during preparation 2 and/or decomposition of certain Tc-99m ra- Inadequate Stannous:Technetium Molar diopharmaceuticals. Impurities that are hy- Ratio drophilic, ionized, non-protein bound, and Tc-99m is obtained from Mo-99/Tc-99m less than 5,000 daltons molecular weight tend generators as sodium pertechnetate (i.e., + - to be excreted in the urine by glomerular fil- Na TcO4 ), a chemical form in which techne- tration.5 On the other hand, impurities that tium (Tc) has an oxidation state, or valence, are lipophilic, possess both polar and nonpo- of 7+ (VII). This chemical form of Tc is lar groups, and have a molecular weight of relatively non-reactive and is not chelated by 300-1,000 daltons tend to be excreted by the other ligand molecules. Hence, for nearly all liver into the bile.5 To describe yet another Tc-99m labeled radiopharmaceuticals, the potential problem, Tc-99m can adventitiously Tc(VII) pertechnetate species must first be radiolabel red blood cells if stannous ion and reduced to a lower oxidation state, such as pertechnetate are both present in the circula- (I), (IV), or (V), using stannous ion (i.e., tion in sufficient concentrations. Sn2+) as a reducing agent. Once in a reduced Many of these potential problems can be oxidation state, the Tc is more reactive and detected by the routine, standard practice of can be readily chelated by various ligand performing quality control testing on each molecules to form Tc-99m labeled radio- radiopharmaceutical preparation and thereby pharmaceuticals. For these reactions to pro- assuring that it complies with applicable ceed with near-complete yield, the amount of specifications for purity before it is adminis- stannous reductant must be sufficient to inter- tered to patients. Unfortunately, some prob- act with all of the pertechnetate; i.e., there lems are not detectable by routinely used must be an adequate stannous:technetium mo- quality control techniques, occur after dis- lar ratio. pensing, occur in vivo, or are otherwise un- One exception to this radiolabeling proc- known at the time of use. Therefore, knowl- ess is Tc-99m sulfur colloid. This particular edge of common problems is essential for radiopharmaceutical involves chemical cova- nuclear medicine personnel, including nu- lent bonds in the formation of technetium clear pharmacists, who are involved in trou- sulfide molecules rather than coordination ble-shooting images with unexpected biodis- complexation with chelating ligands as de- tribution.