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Home , Gamma camera, Nuclear medicine, Nuclear pharmacy, Radionuclide, Radiopharmaceutical

Eur e opea icin n Association of Nuclear Med

The Radiopharmacy A Technologist’s Guide

Produced with the kind Support of Contributors

James R Ballinger, PhD Helen Ryder Chief Scientist Clinical Specialist Guy’s and St Thomas’ NHS Foundation Trust Dept. of Diagnostic Imaging London, United Kingdom St. James’s Hospital Dublin, Ireland Clemens Decristoforo, PhD (*) Chair of the EANM Radiopharmacy Committee Tanja Gmeiner Stopar, PhD Clinical Department of Nuclear Member of the Education Board, Medical University Innsbruck EANM Radiopharmacy Committee Innsbruck, Austria Radiopharmacy, Head University Medical Centre Ljubljana Brit Farstad Department for Member of the EANM Radiopharamcy Committee Ljubljana, Slovenia M.Pharm/Radiopharmacist Department Head, Laboratories Wim van den Broek Institute for Energy Technology Chair of the EANM Technologist Committee Kjeller, Norway Chief Technologist Dept of Nuclear Medicine Brendan McCoubrey University Medicine Centre Safety Officer Nijmegen, The Dept. of Diagnostic Imaging St. James’s Hospital Editors Dublin, Ireland Suzanne Dennan Geraldine O’Reilly, PhD Vice-Chair of the EANM Technologist Committee Acting Radiographic Services Manager Advisor Dept. of Diagnostic Imaging Dept. of Medical and BioEngineering St. James’s Hospital St. James’s Hospital Dublin, Ireland Dublin, Ireland

Clemens Decristoforo, PhD *

This booklet was sponsored by an educational grant from Lantheus . The views expressed are those of the authors and not necessarily of Lantheus Medical Imaging.

2 Imprint References Brendan McCoubrey. . &Administration Record Keeping Chapter 6 -Radiopharmacy: Tanja GmeinerStopar . . . BloodLabelling Chapter 5 –Radiopharmacy: Helen Ryder & Kits TechniquesChapter 4 -Radiopharmacy: . O’Reilly Geraldine . Preparing &DispensingRadiopharmaceuticals Chapter 3 -Radiopharmacy: Ballinger.James . Design Chapter 2 -Radiopharmacy FarstadBrit Chapter 1 -Radiopharmacy Technology Clemens Decristoforo. . Introduction Wim vandenBroek. . Foreword Contents ...... 3 51 49 41 33 22 16 12 6 5 4 EANM Foreword Wim van den Broek

Since it was formed, the EANM Technologist should be provided for all staff working in ra- Committee has been devoted to the improve- diopharmacy departments in the aspects of ment of nuclear medicine technologists’ quality assurance in which they are involved. (NMTs’) professional skills. Publications that will This includes: preparation, release, quality con- assist in the setting of high standards for NMT’s trol and analytical techniques, cleaning, trans- work have been developed and since 2004 portation, calibration of equipment (especially a series of brochures, “Technologists Guides”, for the measurement of radioactivity), working have been published yearly. This booklet practices in the radiopharmacy, preparation of about radiopharmacy is already the fifth vol- the individual doses, documentation, hygiene, ume. The new and stricter regulations in the pharmaceutical microbiology, and microbio- field of preparation of logical monitoring. Often a Nuclear Medicine changed the daily practice in the radiophar- Technologist is the person who is involved macy in the last 5 years. in the preparation and quality control of the radiopharmaceuticals. Nuclear medicine is a multidisciplinary special- ty in which medicine, physics and I am grateful for the effort and hard work of all are involved. The Radiopharmacy is an integral the contributors, who are the key to the con- part of a nuclear medicine department and its tents and educational value of this booklet. prime responsibility is the preparation of high The most essential and relevant aspects of ra- quality radiopharmaceuticals, the base for a diopharmacy in daily practice are emphasised high quality nuclear medicine examination. here. This booklet is prepared in cooperation The majority of these radiopharmaceuticals with the Radiopharmacy Committee of the is mainly used for diagnostic imaging, which EANM. This Committee is very active and criti- is the main activity of nuclear medicine. Ra- cal in the field of regulations and guidelines for diopharmaceuticals are medical products the production of radiopharmaceuticals and defined in the European directive 2004/27/ constantly proposes practical solutions. Many EC amending the directive 2001/83/EC. As in thanks to Suzanne Dennan who coordinated other disciplines the complex changes driven this project. by European legislation had their impact on everyday practice in the preparation of radio- With this new booklet, the EANM Technolo- pharmaceuticals. gist Committee offers to the NMT community again a useful and comprehensive tool that Only trained people should be responsible for may contribute to the advancement of their and participate in the preparation and qual- daily work. ity control of radiopharmaceuticals. Training

4 dedicated to radiopharmacy practice. dedicated to radiopharmacy is TechnologistsGuides the of issue current the Thereforelabelling. cell and dispensing of tion ing eluting generators, prepara - of conventional radiopharmaceuticals includ- handling and preparation the for true cially espe is This departments. medicine nuclear within services radiopharmacy for the backbone are countries many in Technologists Europe. over all variability great a shows still practice radiopharmacy as preparation maceutical radiophar for standard reference general a as serve These lines/gl_radioph_cgrpp.php). (http://www.eanm.org/scientific_info/guide radiopharmaceuticals PET and conventional of preparation the in standards quality the describing Practice” Radiopharmacy Good “Current for guidelines general issued has recently therefore EANM the of Committee Radiopharmacy The important. increasingly becoming are preparations pharmaceutical of field the in especially assurance quality of nologists Guide on the Radiopharmacy. Issues Techexcellent - this for EANM the of mittee I want to congratulate the Technologists Com - Clemens Decristoforo, PhD Introduction 99m Tc-radiopharmaceuticals from kits, kits, from Tc-radiopharmaceuticals - - - 5 only provide valuable information and quick and information valuable provide only not will booklet this that confident very am I andtechnologists.both radiopharmacists field,the in Europeanbyexperts written tion aration and dispensing as well as documenta- nologists such as radiopharmacy design, prep topics of daily radiopharmacy practice of tech- relevant all of chapters contains booklet This rope. Eu- throughout standards equal to practice quality standards and to bring radiopharmacy a practice,” “goodradiopharmacy describe to for guidance provideto intends series this of able part of these initiatives. The current issue valu- a been has Sub-Committee Eductional series of “Technologists Guide” booklets by the The practice. daily in standards quality high support to and technologists of skills sional profes- promoting in active very been has EANM the of TechnologistsCommittee The in nuclearmedicine. quality standards of practices radiopharmacy tice, but also will help to continuously improve prac- daily in arising problems for reference - EANM Chapter 1 – Radiopharmacy Technology Brit Farstad

Radiopharmacy A radiopharmaceutical can be as simple as a Radiopharmacy encompasses studies related radioactive element such as 133Xe, a simple salt to the pharmaceutical, chemical, physical, such as 131I-NaI, or a labelled compound such biochemical, and biological aspects of ra- as 131I-iodinated proteins and 99mTc-labeled diopharmaceuticals. Radiopharmacy com- compounds. prises a rational understanding of the design, preparation and quality control of radiophar- Usually, radiopharmaceuticals contain at least maceuticals, the relationship between the two major components: physiochemical and biological properties of radiopharmaceuticals and their clinical appli- • A radionuclide that provides the desired cation, as well as radiopharmaceuticals chem- radiation characteristics. istry and issues related to the management, selection, storage, dispensing, and proper use • A chemical compound with structural or of radiopharmaceuticals. chemical properties that determine the in vivo distribution and physiological behav- Characteristics of radiopharmaceuticals iour of the radiopharmaceutical. A radiopharmaceutical is a pharmaceutical that, when ready for use, incorporates one Radiopharmaceuticals should have several or more (radioactive ). specific characteristics that are a combination Radiopharmaceuticals are used for diagnosis of the properties of the radionuclide used as or therapeutic treatment of human ; the label and of the final radiopharmaceutical hence nearly 95% of radiopharmaceuticals are molecule itself. used for diagnostic purposes, while the rest is used for . Decay of radionuclides Radionuclides are unstable nuclei that are sta- Radiopharmaceuticals usually have no phar- bilised upon . Approximately macologic effects, as they are used in tracer 3000 have been discovered so far; quantities. There is no dose-response relation- most of these are unstable, but only about 30 ship in this case, which thus differs significantly of these are routinely used in nuclear medicine. from conventional drugs. Most of these are artificial radionuclides, which may be produced by in nuclear re- Radiation is an inherent characteristic of all actors, , or large linear accelerators. radiopharmaceuticals, and patients always re- ceive an unavoidable radiation dose. In the case A radionuclide may decay by emitting differ- of therapeutic radiopharmaceuticals, radiation ent types of ionising radiation: alpha (α), beta is what produces the therapeutic effect. (β-), (β+) and gamma (γ) radiation.

6 still are phase clinicaltrials. inearly they are mainly used for research purposes, or purposes. Their clinical use is very limited, and therapeutic for only used are diameters), cell few a (only area small very a on energy its of in matter due to their mass, thus leaving much range short very a have and monoenergetic is emitted. Alpha emitters, which are with the same charge and mass as an chargednegatively a decay beta .In is a containing two and two an from the nucleus. This particle is characterised by the emission of that ofasimpleradiologyinvestigation. to compared be can patient the by received in such small quantities that the radiation dose keV. Normally, these radiopharmaceuticals are 150 around is equipment medicine nuclear (SPECT) conventional for energy ideal The patient. the of body the outside detected be to enough powerful be should rays gamma produced finally the radiopharmaceuticals, magneticradiation. diagnosticin used When electro as characterised is radiation Gamma radiationdamageto specificcells.is infact decay (alpha or beta) since the intended effect should pharmaceuticals decay by particulate radio therapeutic hand, other the On ticles. par beta even or alpha emit never by gamma emission or , and decay should radiopharmaceuticals agnostic fortherapy.or fordiagnosisDi- either used is radiopharmaceutical the radionuclide, the of characteristics radiation the on Depending - - - 7 1 Ci=37GBq disintegration per second (dps). Normally, ac- as the SI-unit. One is defined as one (Bq) in expressed is Radioactivity units Radioactivity cals for diagnostic by imaging. purposes - radiopharmaceuti label to used are emitters Positron directions. opposite in emitted are ed, giving rise to two of 511 keV that combine with and are thus annihilat At the end of the path of β The range of a positron is very short in matter. Positron (β peutic purposes. used in radiopharmaceuticals mainly for thera - also are radionuclides emitting Beta energy. their on depending 100μm) – (40 matter in ferent energy levels, and have different range (β beta by disintegrate radionuclides rich by t its initial activity to one half. It is usually denoted which is defined as the time required to reduce Every radionuclide is characterised by a half-life, =2,7x10 1 Bq andtheCiisasfollows:the Bq between equivalence The . of g one sions.representsCi One disintegrationthe of occa- some in used is (Ci),which called radioactivity for non-SI-unit a is There (GBq). gigabecquerels or (MBq) megabecquerels of tivities used in radiopharmacy are in the range ½ , andisuniquefor agiven radionuclide. - ) decay. Beta emitters represent dif- represent emitters . ) + Chapter 1 – Radiopharmacy Chapter 1–Radiopharmacy Technology ) decay occurs in rich nuclei. -11 Ci + -

particles, particles, - EANM Principles of radiation protection • Time: The shorter the time of exposure to Production, transportation and use of radio- radiation, the lower the dose to the op- pharmaceuticals, as radioactive products, are erator. governed by regulatory agencies dealing with radiation protection and nuclear safety. Only • Distance: The radiation dose decreases licensed personnel in an authorised facility with a factor equal to the square root of are authorised to handle and use radiophar- the distance from the radiation source. The maceuticals. operator’s distance from the source can be increased by using forceps, tongs, or The general principles of radiation protec- manipulators in handling the radioactive tion are: material.

• Justification:All procedures involving ra- • Shielding: The radiation dose can be re- dioactive material must be justified. duced by placing shielding material be- tween the source and the operator. For • Optimisation: The to protection against gamma radiation, walls any individual should be as low as reason- made of heavy concrete or bricks are ably achievable. This principle is the widely used. For transport containers, material known ALARA concept (as low as reason- such as may be used for higher able achievable). energy gamma irradiation radionuclides, giving a higher shielding per weight unit • Limitation: The radiation dose received when compared to lead. by the personnel handling radioactive material will never exceed the legally es- Formulation and production of tablished dose limits. radiopharmaceuticals When designing a radiopharmaceutical, one When planning facilities and procedures for should have in mind the potential hazard the handling of radioactive materials according product may have to the patient. The goal to the ALARA principle, it is important to keep must be to have a maximum amount of pho- in mind the basic principles for reduction of tons with a minimum radiation exposure of radiation doses: the patient.

8 level chemistry andin level chemistry tracer in important added.particularly is This be to component each of amount the know to needs Furthermore,one partners. two the from knowledge of the chemical properties of molecule to be labelled. This may be assessed whether the label can be incorporated into the is consider to criterion first the prepared, be to is compound labelled a When . of groups or atoms radioactive different or lar of atoms of a molecule are substituted by simi- In a radiolabelled compound, atoms or groups be large. the target-to-background activity ratio should organ/organthe system. of out Thus,leaking potential chemical carrier, and also the rate of organ an in a for uptake specific the toknow important therefore is It organ. target the of pictures the of details structural the obscure can areas non-target from activity the since calised preferentially in the organ under study lo is radiopharmaceutical the that desirable is it diagnostics, in use for also But therapy. portant when using radiopharmaceuticals for im- particularly body.is the This of parts and organs other of irradiation minimise to order in possible, as specific as be should activity there.stays radio radioactivity of uptake The the sure make to and organ, target the to ity - radioactiv the carry to is diopharmaceutical ra- a in molecule carrier the of function The 99m Tc-chemistry. - - 9 As the radiolabelled substances emerge from - Ra out. carried be to operations the suit to maintained and constructed, designed, ises prem- on place take must production scale large- and small- hazardous. Both potentially is radiopharmaceuticals of Manufacturing • • aspects: important two or both. When doing this, one has to consider increasing the of the product, by or batches produced the of volume total uct. This can be done either by increasing the need for scaling up the batch size of the prod - a be will there clinics, the to laboratory the to eachradionuclide. any time, and the radiotoxicity grading given of the radionuclides various to be handled at amount the to according classified normally ratories must be fulfilled. Such laboratories are design and classification of radioisotope labo tories”. National regulations with regard to the designed and approved “radioisotope labora- specially in used be only must radionuclides that stipulate regulations protection diation of radioactivity. tion due to handling of increased amounts protec- operator additional for need The uct itselfdueto possibleradiolysis.uct oftheprodThe influenceonthestability - Chapter 1 – Radiopharmacy Chapter 1–Radiopharmacy Technology - EANM Premises must be designed with two impor- radiation protection to personnel and the tant aspects in mind: environment. Documentation is an essential part of a quality system. Its purpose is to define • The product should not be contaminated the control system, to reduce the risk of error by the operator. that is inherent in oral communication and to ensure that detailed instructions are avail- • The operator and the environment should able to personnel. The documentation system be protected from by the should allow tracking of use and disposal of radioactive product. any batch.

This is the basic principle of GRP – Good Radio­ Radiopharmaceuticals are a special form of pharmaceutical Practice. drugs that require much more handling im- mediately before administration to the pa- Quality considerations tient, when compared to other drugs. Due The key elements of GRP comprise a previ- to the short half life of the radionuclide, it is ously defined manufacturing process known necessary for the final preparation of many to lead to a radiopharmaceutical of the de- radiopharmaceuticals to take place shortly fined quality administered to the patient in before use. Only a minor proportion of all ra- the prescribed dosage and form. GRP is carried diopharmaceuticals is delivered to hospitals in out and recorded by trained and qualified staff a ready-for-use-form. Handling of radiophar- provided with the necessary facilities, includ- maceuticals in hospitals is thus an integral part ing adequate premises, suitable equipment, of the system by which the quality of these correct materials and established procedures pharmaceuticals is established. in written form. Quality must also be main- tained during transportation and storage. Quality control of radiopharmaceuticals All quality control procedures that are ap- Training and qualifications should cover gen- plied to non-radioactive pharmaceuticals are eral principles of GMP (Good Manufacturing in principle applicable to radiopharmaceu- Practice) and radiation protection. All training ticals. In addition, tests for radionuclidic and must be recorded. Premises and equipment radiochemical purity must be carried out. must have a layout and design that minimise Furthermore, since radiopharmaceuticals are the risks of errors by avoiding cross-contam- short-lived products, methods used for qual- ination and build up of dust and dirt, as well ity control should be fast and effective. Still, as permit effective cleaning and maintenance. some radiopharmaceuticals with very short They must also be designed to give proper half-lives may have to be distributed and

10 are obtained. resultstest unsatisfactory if taken be suresto mea- describes which procedure a include should system control quality The product. stated for in insert the the package particular a simple quality control procedure should be Pharmacopeia (BP, USP etc.). For labelling kits, given in the European Pharmacopeia, or other are radiopharmaceuticals used currently the quality control testing procedures for most of istration (labelling kits).The specifications and admin- to prior department the in labelled is product is a ready-for-use-form, or the product the whether on depends control quality the of complexity The patient. the to istration beforecontrolproducts forof quality admin- programme a have should harmaceuticals radiop with dealing departments Hospital not beencompleted. tion even though all quality control tests have documenta- batch of assessment after used - 11 Chapter 1 – Radiopharmacy Chapter 1–Radiopharmacy Technology

EANM Chapter 2 – Radiopharmacy Design James R. Ballinger, PhD

Facilities The radiopharmacy should be conveniently Although many of the principles of radiophar- located for deliveries and shipments (if supply- macy design are universal, there may be dif- ing external units). There should be arrange- ferences between countries in how rigorously ments for receipt of out of hours deliveries, these principles are regulated. The radiation such as a locked cupboard adjacent to the aspects are covered in the EC Euratom Direc- unit but not requiring direct access to the tive [1] while pharmaceutical manufacturing radiopharmacy by unauthorised personnel is controlled under EudraLex [2]. The EANM such as couriers. Radiopharmacy Committee has issued guid- ance on Good Radiopharmacy Practices [3] Layout which addresses both aspects. With respect Restricted access is important, from both a to both facilities and operations, there can be radiation security and pharmaceutical manu­ conflicting requirements between radiation facturing point of view. Only persons with safety and aseptic processing. Another impor- business in the radiopharmacy should be tant consideration is complete segregation allowed access. Within the radiopharmacy, between radiopharmaceutical preparation there will be further restriction of access to (aseptic processing) and blood cell labelling, the clean areas. The principle is moving from to minimise the risk of cross contamination. dirty to clean areas with appropriate change of apparel and sanitation of materials at each In general, the radiopharmacy should be at interface. The dirty areas include delivery and one end of a nuclear medicine/ de- dispatch, an office for preparation of paper- partment rather than in the middle. Indeed, work, a supplies store, a waste store, and a it is best if it is on an outside wall as there QC laboratory. It is particularly important to is less concern about shinethrough of radia- unpack supplies in the dirty area where there tion. Although high levels of radioactivity are is bulk storage; only minimal supplies are kept handled, in most cases local shielding is used in the clean area. Some radiopharmacies may (e.g. around generators and individual vials) have a separate area for handling of 131I. The rather than extensive shielding in walls. clean areas include a 99mTc dispensing room, a support room, and a separate blood cell la­­ belling facility. The layout should enable an orderly flow of work, both within and between rooms.

12 allow ofthe determination Transport Index. a dose rate monitor (i.e. calibrated in µSv/h) to radioactivematerial isshipped, there must be the boundary of the radiation controlled area. If check for contamination within the unit and at Radiation survey meter(s) must be available to andnotshared withoutsideusers. harmacy ment should be dedicated to use in the radiop equip This system). radio-HPLC and analyser advanced laboratories may have a multichannel chromatogram scanner, ; more (radio equipment radioanalytical appropriate and centrifuge), balance, (e.g. equipment tory labora- chambers), (ionisation calibrators dose more or one includes equipment Standard Equipment andfittings Figure 1:Samplelayout ofaradiopharmacy radiopharmaceuticals. of radiolabelling and handling for required areas working ferent dif- of separation ideal with radiopharmacy large a of layout sample a presents 1 Figure 99m Tc and other SPECT SPECT other and Tc - - - 13 monitoring. This can be as simple as manual as simple as be can monitoring. This aresupplies stored haveshould temperature and Refrigerators other areas where sensitive to minimise dirt collection. fixtures should ed sheet vinyl. Corners should be coved (curved) non absorbent, cleanable material such as weld - ceiling) with a smooth, continuous, impervious, The clean areas should be lined (floor, walls, and could becomeradiationhazards themselves. they as used generally not are Filters stack. and care must be taken in the location of the The exhausted air is vented to the atmosphere Volatile materials such as recorder software. ormonitoring chart a to output electronic an or mometer maximum temperatures on a calibrated ther and minimum of basis daily a on recording hair cover, andgloves. minimum: clean low-lint lab coat, shoe covers, two sides. Changing on entry will involve, at a or at least a line on the floor, to demarcate the have interlocking doors and a physical barrier, should rooms Entry/change contact. direct allowing without room next the into passed locking doors so supplies can be sanitised and inter with hatches transfer be should There for leadshielding.ditional support ad- require may and laminate) over preferred is (solid material impervious of made be must be recessed and flush with the surface. Benches cupboard with a minimum inflow of 0.5 m/s. 0.5 of inflow minimum a cupboardwith fume a in handled be should solvents ganic Chapter 2 – Radiopharmacy Design Chapter 2–Radiopharmacy 131 I products and or - - - EANM Aseptic manipulations should be performed It is simplest to dispose of all sharps into rigid either in a pharmaceutical isolator or a laminar biohazard containers behind a lead shield. airflow hood. Once the radioactivity has decayed to back- ground levels, the containers are disposed as The bulk of the work for the foreseeable future biohazard waste. Radionuclides should be will continue to be reconstitution of kits with segregated by half life to minimise the build 99mTc pertechnetate. Thus, a single workstation up of waste. is adequate even if there is occasional handling of other radionuclides (e.g. preparation of 111In The blood labelling suite will require a vari- pentetreotide or 90Y ). able speed centrifuge capable of accepting a However, if the usage of other radionuclides is range of tube sizes. Ideally the centrifuge will more extensive, a separate workstation should be located within the workstation, to minimise be provided. In addition to minimising the po- the number of transfers out of the Grade A tential of cross contamination of 99mTc prod- environment. ucts with longer lived and/or particle emitting radionuclides, it also reduces the risk that a Area designation major spill of one of these radionuclides could A radiation controlled area is one in which a impede 99mTc dispensing for a number of days. full time worker might receive an exposure of In the future, some products such as 90Y or 6 mSv/yr whole body or 150 mSv/yr extrem- 177Lu labelled peptides might be prepared by ity. For a radiation supervised or monitored automated synthesis units located in a sepa- area, the exposure limits are 1 mSv/yr whole rate workstation. body or 50 mSv/yr extremity. Because of the presence of generators and the amount of In general, radiation safety is maintained by radioactivity handled, the hot lab will be des- local shielding (e.g. vial shields, syringe shields, ignated a controlled area. Other areas may be bench top shields) rather than shielding in the classified as supervised. walls. The waste store may require shielding, as may an area where high levels of radioactivity Radiation designated areas must be physically are handled if there is a significant radiation demarcated and have signs indicating the field in the adjacent room. The 99Mo/99mTc type of hazard. There should be washing and generator usually requires additional exter- changing facilities available at the perimeter; nal shielding. and radiation monitoring for contamination must be performed. Eating and drinking is prohibited in designated areas.

14 inspectors. of sets both satisfy to balance delicate a find must managers Radiopharmacy cleanroom. a near anywhere sink a want don’t spectors in- the while area, controlled the of perimeter the at facilities handwashing requires Radioprotection dose. radiation the share to staff of rotation a be should there radioprotection for whereas staff, trained of of view, there should be a minimum number point pharmaceutical Fromroom.a pressure positive a within isolator pressure negative a microbes.ingressof mise compromiseis The mini- pressuretopositive at are units aseptic pharmaceutical while discharge), aerosol or to the outside world (containment of gaseous relative pressure negative at be should area conflicts. For radioprotection, the production are there areas, these within even However, record isimportant. keeping meticulous and required are staff trained ist Special- boxes. hoods/glove containment of use the and system handling air separate a with both radioactivity and microbes, as does contamination cross minimises equipment, tivities, with change of apparel and dedicated ac- of segregation example, For agreement. systems.tory However, there are also areas of regula- different of requirements the tween be conflicts be can there above, noted As regulations Conflicts between radiation and aseptic - 15 Chapter 2 – Radiopharmacy Design Chapter 2–Radiopharmacy

EANM Chapter 3 – Radiopharmacy Preparing & Dispensing Radiopharmaceuticals Geraldine O’Reilly, PhD

Introduction Most radiopharmaceuticals are administered The radiopharmacy would normally be desig- by IV injection; so good pharmaceutical prac- nated as a controlled area; and access will be tice is an important consideration in their restricted. Only properly trained staff should preparation. All manipulation of radioactive be permitted to work in the radiopharmacy; materials should be carried out, using asep- and strict adherence to work procedures is tic techniques, within the shielded contained essential. There are three fundamental pa- workstation or laminar flow cabinet (LAFC) rameters that affect staff doses in the radio- (Figure 1). No food or drink, cosmetic or smok- pharmacy: ing materials, crockery or cutlery should be brought into an area where unsealed radioac- 1. the distance between the staff member tive substances are used. and the source, 2. the time spent manipulating the source Figure 1: Laminar flow unit for preparation of and 99mTc radiopharmaceuticals 3. the amount of shielding used to reduce the dose rate from the source.

Sometimes there is a trade off between these parameters as using more shielding might in- crease handling time. With this in mind, care- ful design of procedures should optimise the workflow. Skill and expertise of the staff carry- ing out the procedures are also important fac- tors. Thus, it is crucial that staff are adequately trained. Personnel monitoring Work practices in the radiopharmacy should All staff classified as radiation workers must be standardised and incorporated in standard wear a personal dosimeter (TLD, film badge, operating procedures (SOPs). These proce- electronic dosimeter). In addition to their regu- dures should be documented and made lar whole body dosimeter, staff preparing and readily available to those working in the ra- handling radioactive materials should wear a diopharmacy. This will ensure harmonisation finger TLD to monitor extremity dose. Prior to of practice and maintenance of standards. Ac- each use, the TLD should be wiped, using an curate and comprehensive record keeping is alcohol wipe, and worn inside the glove. Upon an essential part of good work practice in a leaving the preparation area, the finger TLD radiopharmacy. should be removed and appropriately stored.

16 purpose, andshouldinclude thefollowing: vided with equipment kept specifically for this unsealed radioactive substances should be pro areasotherworkmanipulationforandries of dose.Laborato reducingstaff on impact cant signifi- a have can materials, radioactive dling han- when equipment, protective of use The Protective equipment at background radiationlevels. waste until monitoring confirms that they are disposal, they should be stored as radioactive disposable gowns should be removed. Prior to radiopharmacy, the leaving Upon gloves. of Hands should be washed again after removal materials/surfaces within the radiopharmacy. other any handling/touching before waste radioactive as of disposed and removed be always must gloves materials, radioactive rate before entering the LAFC. After handling evapo to allowed and gloves onto rubbed be should rub Alcohol cabinet. the within filters air the of clogging prevent to order in or contained workstation must be powder free maintaining sterility. Gloves worn in the LAFC of terms in benefits offer gowns Disposable tion and dispensing of radiopharmaceuticals. prepara - for worn be should gowns or coats Protective strapping. adhesive waterproof a incorporate should Dressings covered. be should skin the in break or cut any handled, ters an area where radioactive substances are en- person a Before thoroughly. hands their radio pharmacy, staff the should ensure that they wash in work commencing to Prior Protective clothing Chapter 3 – Radiopharmacy: Preparing Radiopharmaceuticals &Dispensing Chapter 3–Radiopharmacy: ­ - - - 17 Unshielded syringes or vials should never be never should vials or syringes Unshielded 6. 5. 3. 2. required should be assembled and placed in placed and assembled be requiredshould materials the of all radiopharmaceuticals, of Before starting the preparation and dispensing General Work procedures with localrecommendations. accordance in regularly cleaned be should the laminar flow cabinet when not in use and ceuticals. Equipment should be stored outside - radiopharma of manipulation during used 4. 1. terials inthedosecalibrator.terials be used to place and remove unshielded ma- handled directly. Long handled tongs should say. Unshielded vials or syringes should not be shielded while handling, except during an as- ringes containing radioactive liquids must be shields for assay, inspection or disposal. All sy- their fromremoved be only should vials and handling; while shielded be must materials radioactive containing vials All 2). (Figure workstation/LAFC contained the to close or

drip drip trays for minimising the spread of con- decontamination kit and carriers shielded syringe tamination inthecaseofspillage, vial shields, shields,syringe source, for exampletongs andforceps, tools for maximising the distance from the

EANM Work procedures should be designed so as Reconstitution of pharmaceuticals to minimise exposure from external radiation The manufacturer’s recommendations should and contamination. Care must be taken to pre- be followed closely as many pharmaceutical vent spillage from occurring. All manipulation kits have specific reconstitution instructions in for dispensing radioactive materials should terms of the activity and volume to be added be carried out over a drip tray, in order to to the kit. Recommended incubation times minimise the spread of contamination due also vary and must be adhered to. Some ra- to breakages or spills. Should a spill occur then diopharmaceuticals must be refrigerated after it should be cleaned up before proceeding preparation. Therefore consideration should be any further. All items that might be contami- given to the provision of suitably shielded re- nated should be removed from the affected frigeration facilities. Most radiopharmaceuticals area and stored safely. Care should be taken are reconstituted with 99mTc; and this assump- doing this, in order to minimise the spread tion applies to the following paragraphs. of contamination. As with all spills, it is more convenient to allow natural decay to take care Protective caps should be removed from the of the contamination, if the items are not re- pharmaceutical vials; and the vials should be quired immediately. For those items that are placed in the appropriate labelled vial shields. needed, they should be cleaned with alcohol The rubber septum of each pharmaceutical vial swabs taking care not to spread the contami- should be swabbed with alcohol; and the alco- nation. Using multiple swabs which are then hol should be allowed to evaporate (Figure 3). disposed is the most effective way to remove contamination. • Shielded 10ml or 5ml syringes capped with 21G needles are generally used to recon- Figure 2: Preparation of work area stitute the pharmaceuticals. (courtesy of VirRAD) • The appropriate activity of 99mTc solution should be added to each shielded phar- maceutical vial; and the pharmaceutical should be allowed to incubate for the specified length of time.

• Having introduced 99mTc solution to a pharma- ceutical vial, the needle should not be placed back into the shielded elution vial. In the event that additional 99mTc solution is required, a new syringe and needle must be used.

18 (courtesy of (courtesy VirRAD) Figure before 3:Disinfection ofakit use • • recorded in the laboratory log book. logbook. recorded inthelaboratory be should pharmaceutical each to added of volume and activity The facturer ofthepharmaceutical. manu- the by recommended specifically used be not should and mended In general, breather needles are not recom - be done gradually as the solution is added. can This time. same the at air of volume equivalent an withdrawing by pressure equalise to necessary be may it vial, a to introducing When 99m Tc solution or saline or Tcsolution Chapter 3 – Radiopharmacy: Preparing Radiopharmaceuticals &Dispensing Chapter 3–Radiopharmacy: 99m Tc solution Tc unless 19 • • • • Preparation ofpatientinjections • • ne h ptet neto i prepared, is injection patient the Once is below 1ml. obtained is activity required the which in used to increase the volume if the volume volume should be followed. Saline may be this: the manufacturer’s instructions on the in prepared usually are injections Patient time. atthespecifiedinjection ity requiredthe - of 10% activ within be must patient each for withdrawn activity The log. radiopharmacy the in recorded and measured be must activity patient Each with 21G. drawn using shielded 2ml syringes capped with- are activities patient elapsed, has If, at any time, there is a droplet of liquid vis- tip.the syringe plunger sufficiently so as to pull liquid from the withdraw needles, changing When is capped. needle the that ensure air, the expelling air in the syringe must be expelled. be must When syringe the in air the and gauge,appropriate the of needle the green needle must be replaced with a to exceptions are There1ml. of volume a time incubation recommended the After and cap. needle the cap,replace needle the in ible

EANM • Each patient injection must be labelled The waste container in the workstation should with an appropriate label detailing the not be allowed to overflow and should be patient name, scan type, activity to be ad- emptied regularly. The bin is best emptied ministered, date and time of injection. before starting work in the cabinet, when the waste in the bin has decayed over night. Waste management procedures Non- should be separated Segregation of waste according to half-life from radioactive waste to minimise storage is good practice and can reduce the length requirements; and it should be disposed of of time that waste arising from shorter lived as normal hospital waste. Shielded waste bins isotopes has to be stored. should be lined with plastic liners that can be easily removed when full. Paper waste Any gloves used in the cabinet or used to 99m is the main isotope in use handle blood or isotopes will be considered in the radiopharmacy: the duration of stor- to be contaminated. Paper tray liners in the age will be determined by its half life of 6.02 cabinet or paper used to clean surfaces in hours. Longer lived waste should be stored the cabinet are also considered to be con- separately. Radioactive waste generated daily taminated. Contaminated gloves and paper within the radiopharmacy includes syringes, should be disposed in a shielded bin in the elution vials, pharmaceutical vials, needles and pharmacy, as long as there is no biological swabs. Waste arising from the preparation and contamination (blood or plasma). Otherwise dispensing of radiopharmaceuticals should this waste should be placed in a sharps bin, us- be primarily disposed in the waste bin built ing tongs. For long term storage of waste, the into the contained workstation/LAFC. Some waste should be removed from the shielded bulky items such as paper waste and gloves bin, labelled with details of the contents and may be disposed in a shielded waste bin in the stored as radioactive waste in a designated pharmacy, as long as there is no risk of con- store. taminating the room by removing them from the cabinet. Radioactive waste contaminated Sharps bins by blood (e.g. syringes following cell labelling Syringes, needles, butterflies etc. should be procedures) should not be left in the worksta- disposed of after use to shielded sharps bins. tion but removed to a shielded bin. Bins should not be allowed to overfill. Full sharps bins should be closed, marked ‘radio- active’, dated and removed to the radioactive waste store.

20 es with different principal energies, photon principal different with es activity (within 5%). At least two sealed sourc- a given calibrated reference source of known of percent 10 within is activity the that sures of the reference source. The accuracy test en- selected on the dose calibrator should be that isotope reading.The background the record sources from the vicinity of the calibrator and Before starting the QA, remove all radioactive out lessfrequently. carried be may tests Linearity out. carried be should constancy and accuracy operation, system of check daily A energies. of range a over calibrator the of checking allow will are suitable. The use of more than one source Ra-226 or Cs-137 with a relatively long half life Co-57, as such Isotopes source. reference a with regularly checked be should calibrator dose the of constancy and accuracy The Dose calibrator assurance quality shouldbeadhered to.policy disposal waste hospital The waste. hospital in disposal to prior waste, from removed be storage. All radioactive warning labels should in decay of period further a for retained be should background above items Any level. posed of, once it has decayed to background background environment and should be dis- be checked by using a suitable meter in a low stored and monitored regularly. Waste should securely be should - kits ventilation waste, paper bins, sharps - waste radioactive All Disposal ofwaste Chapter 3 – Radiopharmacy: Preparing Radiopharmaceuticals &Dispensing Chapter 3–Radiopharmacy: 21 should beconstantover time. referencethe sourceofactivity the of thatto dose calibrator. The ratio of the values indicated theselectable isotopesareotheronthatfor done be also can recorded.This is indicated the setting is changed to Tc-99m and the value this test, the reference source is left in place; but the most frequently used isotope. To carry out be checked daily for constancy at the setting of long period of time. The dose calibrator should measuring the activity of a known source over a in reproducibility at looks test constancy The lowable 10%). tolerance (typically al- the within be should recorded value The measured. activity the record and calibrator check, place the reference source in the dose accuracy routine the Forthereafter. annually least at and installation, upon accuracy mine 100 keV and 500 keV, should be used to deter one of which has a principal energy between macy records.macy radiophar the of part as stored and mented The results of the routine QA should be docu- shouldnotexceed 10%. activity and known half-life.short indicated between The variation and availability its of because test linearity the ter. Technetium-99m is most frequently used for upon installation and at least quarterly thereaf - The dose calibrator should be tested for linearity activities. measured or administered of use of can indicate the overcorrect activity the range The linearity test ensures that the dose calibrator - - EANM Chapter 4 – Radiopharmacy Kits & Techniques Helen Ryder

Radiopharmaceuticals have been defined as patient movement; or too short a time per ‘radioactive drugs that, when used for the image resulting in poor count statistics. If purpose of diagnosis or therapy, typically elicit the half-life is too long, then there may be no physiological response from the patient.’ excessive radiation exposure to the patient over its period of decay. In the main this is true, and though some 3. High target - background ratio radiopharmaceuticals have been known to The radionuclide is only of use if it accu- cause minor (such as urticaria, mulates within the target organ, and this or changes in blood pressure), these are not is often enhanced by binding the radionu- commonly seen in practice. clide onto a tracer that will take it to the organ under study. The binding should be Ideal radionuclide sufficient that little radionuclide is left free Properties of the ideal diagnostic radionuclide in the body tissues, thus enhancing the include: target-to-background ratio. 4. Low dose rate to both patient and per- 1. Pure gamma emitter, with a gamma en- sonnel ergy within the range of 100 - 250 keV, to To avoid excessive received radiation dose, match the optimum scanning range of a it is necessary to avoid those radionuclides . which have significant particulate emis- The radiation emitted by a radionuclide sions i.e. alpha and beta particles. The short should be sufficient to be detected outside range of emission means that these are the patient for imaging purposes, thus lim- absorbed within the patient, adding to the iting the choices to X-rays or gamma rays. radiation dose with no increase in image However, too high an energy will result in quality. Because of the reality of radiation the penetrating the detector of decay, that is the attempt to balance the the imaging device without being stopped particles in the nucleus, beta rays are often and hence recorded. found as a product of decay. The rate of 2. A half-life which is suitable for diagnostic emission of these rays can be significantly use i.e. 1.5 X test duration lower in two particular decay processes: The half-life of a radionuclide determines isomeric transition and . the rate of radioactive decay. If the half-life 5. Non-toxicity of radiopharmaceuticals is very short, then the activity may have Most radiopharmaceuticals must be inject- decayed to a very low level before imag- ed, with a small amount being ingested or ing can be started. This can result in either inhaled. Thus they must be non-toxic in a long scanning time, where there may be nature, sterile and pyrogen-free.

22 8. 7. 6.

readily bind to a wide variety of compounds compounds of variety wide a to bind readily to ability has tracers.Technetium ‘the 99m to binding for suitable are radioisotopes all Not ae f rprto ad appropriate and preparation of Ease without detrimental effect on the patient. effect on thepatient. without detrimental the patient will result in high-quality images This ensures that the preparation received by laboratory. working reconstitutedthe cal in check each batch of the - radiopharmaceuti to available be should procedures control Quality required. be equipment of variety ‘easeofpreparation’. Nor should complexa stepsdonot usually meet the definition of controlquality requirements. expensive and uneconomical for everyday preparation with other tracers. This can be for or product resultant the as either day, particular a on use for ordered be must aremoment they manufactured and thus ready for use. These are decaying from the trons as specialised units and are shipped the radionuclide. of use economical in results required.This as eluted and facility medicine nuclear a to delivered be may which generator, a from causing physiological changes inthepatient. [1] conditions physiological under Preparation requirements of more than three Inexpensive andreadily available use during Chemical stability Other Other radionuclides are produced in cyclo Many suitable radionuclides are obtainable areradionuclides obtainable suitable Many

without without -

23 generator - radiopharma preparationof forthe nuclides A radionuclide generator is a source of radio generatorRadionuclide moved from the columns as movedcolumns fromthe clear Medicine isthe clear Medicine 1. The most commonly used generator in Nu- radionuclide generators are provided in Table of Examples (parent). radionuclide lived long a from (daughter) radionuclide lived short a of separation the on based is It ceuticals. ing over a solution of sodium chloridesodium(NaCl)solutionof aover ing Molybdenum/Technetium ( radiopharmaceuticals (Figureradiopharmaceuticals 3). the compound to used is eluate resultant the process is known as ‘eluting the generator’ This 2). (Figure and column the across w/v 0.9% as pertechnetate which decays to its daughter radionuclide absorbed sists of an alumina-filled column onto which is The molybdenum/technetium generator con- Table generators 1:Radionuclide Chapter 4 – Radiopharmacy: Kits& Chapter 4–Radiopharmacy: Techniques 99 Mo. The 99m 99 TcO Mo Mo is present as 99 Mo/ 4 - (Figure 1). 99m 99m Tc generator. 99 TcO Mo/ 4 99m - 99m by drawby- 99 Tc is re MoO Tc) 99m 4 Tc Tc 2- - - , EANM Figure 1: Decay scheme for 99Mo and 99mTc Figure 2: Molybdenum/Technetium generator (courtesy of VirRAD)

Figure 3: Eluting the generator (courtesy of VirRAD)

Attach Saline Vial Insert Elution vial Attach Elution vial and wait Remove elution vial and attach in lead shielding until elution is completed protecting vial/Cap

The time of maximum yield of 99mTechnetium is 23 hours, after which the 99mTc appears to decay with the half-life of 99Mo (66hrs). This time of almost one day is therefore eminently suitable for the requirements of the Nuclear Medicine department (Figure 4).

24 • • equilibrium is reached (courtesy of isreachedequilibrium (courtesy VirRAD). • Categories ofradiopharmaceuticals: radiopharmaceuticals from kits • the equilibrium. The generator is eluted daily and activities against time showing transient in Appendix2. provided is activity required the calculate to how of example An kits. proprietary of tion reconstitu- for procedure the details further 1 Appendix Figure5. in outlined are kits and of The basic steps involved in the reconstitution kits: ofproprietary Reconstitution Preparation of Figure 4:Plot of oflogarithm 99m Ready-to-use radiopharmaceuticals Ready-to-use Products requiring significant manipulation requiring heating Kits for preparation kits of Instant 99m Tc radiopharmaceuticals from generators Tc activity grows again until transient 99m Tc- 99 Mo and Mo 99m Tc products 99m Tc 25 radiopharmaceuticals fromradiopharmaceuticals generators andkits • with kits ofproprietary Appendix 1:Reconstitution Figure of 5:Reconstitution • • the in information following the Record ticulum andthyroid . scanning, Meckel’s diver is lung for useful generator low The a and tor ‘low’generator. may have a ‘high’ genera- departments Some kits. the of reconstitution for eluted is generator The • • log: injection every morning and used and morning every Chapter 4 – Radiopharmacy: Kits& Chapter 4–Radiopharmacy: Techniques vial during labelling.vial during tion introduced to each pharmaceutical of volume and activity The The activity andvolume oftheeluate.The activity and salinebottles. the elutionvial, vials pharmaceutical date of The batch number andexpiry 99m Tc 99m - Tc Tc 99m Tc solu- Tc EANM • Remove the flip/ Appendix 2: Calculation of activity foil cap from the pharmaceutical Example calculation of activity to add to vial vial and place Example: What is the minimum activity of 99m the vial in a la- Tc eluate needed to be added to a vial of 99mTc- belled shielded Cardiolite at 8a.m., to obtain five injections of container. Swab 740Mbq each – 2 injections at 8a.m., 3 injec- the rubber septum with alcohol, and al- tions at 11a.m.? low the alcohol to evaporate. The equation to calculate radioactive decay is: • When reconstituting the pharmaceu- -λt tical use a shielded 5ml syringe At = Aoe capped with a green needle. 10ml and 2ml syringes may also 1. Calculating λ be used, depending on the re- λ is the decay constant which for any ra- quired volume. dionuclide is defined as

• The required activity of 99mTc solution may need to be topped up to the required vol- ume with saline.

• Patient injections are typically made up to a volume of 1ml. The re- quired activity of radio-labelled 2. Where Ao = 740MBq, t= -3 pharmaceutical may need to be topped up to 1ml with (When calculating an activity *prior* to the saline. time of known activity, the value of t is nega- tive. To calculate the decay of a radionuclide • All patient injections are to be labelled with *from* a known activity to a later time then t an appropriate label, detailing the patient has a positive value.) name, date and time of procedure, proce- -(0.115)(t) dure type and activity to be administered. At = Aoe -(0.115)(-3) At = Aoe 0.346 99mTc-Cardiolite At = 740 x e

Act...... MBq Date...... At = 740 x 1.413 = 1045.6MBq Pt. Name

26 vial ofCardiolite is: c. tor. Mo-99 is assayed directly in the special lead pig supplied by the manufacturer of the dose calibra- breakthrough:1. Mo-99 QC test procedures for Mo/Tc generator Table ofimpurities 3:Detection b. a. of activity total The at8a.m.is1045.6MBq. per injection Therefore the required activity to be drawn up Table 2:Classificationofimpurities to whetherthisamountisexceeded determine dependent onmanufacturerandage. must not exceed 0.1% of the total the of 0.1% exceed not must Radiochemical Radionuclidic Colorimetric Thin layer chromatography calibrator/multichannelDose analyzer Method Type ofImpurity Chemical

x 4Mq o to netos t 8a.m. at injections two for 740MBq x 2 x 14.Mq o tre netos at injections three for 81045.6MBq x 3 add to vial ofHDP Add (a) to (b) to get total of 4616.9MBq to 11a.m. =3136.9MBq =1480MBq 99m Tc is then assayed directly in the plastic sleeve in the dose calibrator. Theof activity 99m Tc to be added to the to added be Tcto Free 99 Example Al Mo 3+ 99m Tc-pertechnetate 99m Chemical Radiochemical Radionuclidic Type ofImpurity Tc-activity. how differenthave methods calibrators Dose 27 Rationale for performing quality control quality forRationale performing controlQuality intheradiopharmacy briefly outlinedinbriefly Table 3. are impurities these detecting for odologies be distinguished, as outlined in Table 2. - Meth can process imaging the affecting impurities of classifications different Many discomfort. patient and dose radiation increased in ing The procedure must then be repeated result study. non-diagnostic a in result can it pared pre improperly is radiopharmaceutical a If Increased radiationdose;poorimagequality Increased Poor dueto labellingproblems imagequality Effect Poor image quality; increased radiation Poor imagequality; Chapter 4 – Radiopharmacy: Kits& Chapter 4–Radiopharmacy: Techniques 99 Mo Mo - - EANM The timetable of required testing is shown in Table 4, and for optional testing in Table 5.

Table 4: Required QC testing of a 99Mo/99mTc generator Test Frequency Specifications Mo breakthrough Every elution <0.1% of 99mTc activity at time of injection Al3+ ion breakthrough Every elution <10 ppm of Al3+; may be expressed as µg/ml

Table 5: Optional QC testing of a 99Mo/99mTc generator Test Frequency Specifications Hydrolyzed Reduced Tc Every elution < 5% (Reasonable limit)

2. Aluminum ion breakthrough: Figure 6: Aluminium breakthrough test (courtesy of VirRAD) Al3+ ion is measured colorimetrically. A drop of the eluate is placed on one end of a special test paper; a drop of a standard solution of Al3+, concentration 10 ppm, is placed on the other end of the test strip (Figure 6). If the colour at the centre of the drop of eluate is less red than that of the standard solution, the eluate has passed the Aluminum Ion Breakthrough Test. Units may be expressed as ug/ml.

28 distance alongthechromoplate. (Figure 7) the most soluble product moving the furthest plate. The different chemical species separate; the along up migrate or rise to allowed then is solventimmersed. The not is point (origin) placed in a solvent, ensuring that the bottom of the chromoplate. The chromoplate is then (origin) bottom the near applied is tested be to product the of microlitres few a Generally pharmaceuticals. different for produced are differentcommercialand a product, types as The test strip or chromoplate may be obtained testingfor radiochemicalpurity General principles of planar chromatography controlity ontheradiopharmaceuticals. purity, it is important to perform regular qual- dose for the patient. To ensure radiochemical increasedand radiopharmaceutical radiation the of imaging poor be can result A again. if the reduced radionuclide becomes oxidised in the resulting solution. This can also happen some free or unbound technetium is present duction of pertechnetate does not occur and re complete the pharmaceutical, to It can happen that, during the binding of radio its unboundform (i.e. ‘free’radionuclide). pharmaceutical) to the radionuclide present in present in a bound form (i.e. as a bound radio pharmaceutical is the ratio of the radionuclide radio a of (RCP) purity radiochemical The chromatography purity,Radiochemical paperandthinlayer ­ - - ­ 29 marked ontheorigin. marked shown. The sampleisplacedatthepoint position oftheorigin andsolvent front Figure 7:Achromatography withthe strip When the solvent has moved the required the moved has solvent the When ity oftheradiopharmaceutical. ity portion and thus the respective binding qual- be determined the quantity of activity in each front(R vent sol- the by travelled distance the of fraction a as expressed is species radiochemical the of each by chromoplate the along travelled the of surface a gamma camera. The distance on or detector scintillation a under it passing by either radiochromatogram, the scanning by read is this step, next a As dry. to allowed front), then it is removed from the solvent and solvent (the chromoplate the along distance Chapter 4 – Radiopharmacy: Kits& Chapter 4–Radiopharmacy: Techniques f value). Fromvalue). R these f values can values EANM Radiochemical impurities in 99mTc Equipment and location: radiopharmaceuticals The determination of the radiochemical purity Common impurities in 99mTc-kits are 99mTc- in the hospital with TLC can be performed with pertechnetate and 99mTc-colloid. However a little expenditure of material and equipment. number of 99mTc-preparations may contain It should be performed in a dedicated area different impurities that have to be covered with radiation protection and proper ventila- by respective validated tests (e.g. 99mTc-Tartrate tion (organic solvents). in 99mTc-MAG3). A number of recommended chromatography methods are shown below Quantification: in Table 6 and Table 7. A variety of methods may be used to quantify impurities including cut and count in the dose Separation of radiopharmaceutical and calibrator, using dedicated scanner, gamma impurity cameras and others. The differences are in Radiochemical purity testing can be based sensitivity, resolution, linear range, speed, on thin layer or paper chromatography (TLC), availability and practicability and should solid phase extraction methods based on be chosen dependent on available space, cartridges (SPE), filtration methods, HPLC or throughput and general organisation of the electrophoresis. Methods may derive from radiopharmacy. Equipment used for qual- the European Pharmacopeia, the SPC of the ity control should be regularly calibrated. labelling kit or validated literature methods. In Generally, the quantification of the radio­ many cases a variety of methods are available chemical purity is based on the equation for one particular radiopharmaceutical. TLC below. methods and SPE are most commonly used In case the radiochemical purity limit is not and recommendations in this guidance are reached, the preparation has to be discarded based on these methods. and clearly labelled that it may not be used for patient application.

30 Table methodsfor control 6:Recommended quality basedon TLC 99m Pertechnetat 111 99m 99m 99m 99m 99m 99m 99m 99m 99m 99m 99m 99m bodies; HIG,Zevalin MDP, DPD, HEDP In In Tc-monoclonal Anti- Tc-Tetrofosmin Tc-Depreotide Tc-MIBI Tc-EC Tc-MAA Tc-Colloids Tc-IDA-Derivates Tc-HMPAO Tc-ECD Tc-DTPA Tc-Diphosphonates Tc-DMSA 0.1M Na-Citrat pH5/ITLC-SG0.1M Na-Citrat Solid Phase / Mobile Phase Phase /Mobile Solid ITLC-SG/0.9% NaCl ITLC-SG/ 0.9%NaCl Dichloromethane =35:65/ ITLC-SG /Aceton : B) A) Aluminiumoxide Ethanol /Baker B) A) ITLC-SG /2-Butanone ITLC-SG /2-Butanone B) A) B) A) Ethylacetate Silicagel /Baker B) A) B) A) ITLC-SG/ 2-Butanone (50/50) Methanol/1Ammonacetate / ITLC-SG ITLC-SG /saturated NaCl ITLC-SG/ 0.3MAcetic acid ITLC-SG/2-Butanone 50% Acetonitril /ITLC-SG ITLC-SG saturated salinesolution/ ITLC-SG/ 0.9%NaCl ITLC-SG/ 2-Butanone ITLC-SG /2-Butanone ITLC-SG /NaCl ITLC-SG/ 2-Butanone ITLC-SG/ 1MNaAcetate 31 Chapter 4 – Radiopharmacy: Kits& Chapter 4–Radiopharmacy: Techniques pharmaceutical Rf Radio Middle Front Front Front Front Front Front Front Front Front Start Start Start Start Start Start Start Start Start Start Start ­ Rf Impurity Start/Front Front Front Front Front Front Front Front Front Front Front Front Start Start Start Start Start Start Start Start Start EANM Table 7: Recommended methods for quality control based on SPE Radiopharma- Cartridge / Solvent Impurity ceutocal SEPPAK C18 light 99mTc-MAG3 1.) 0.001N HCl, Eluate 2 column/ eluate 1 2.) Ethanol/0,9% NaCl (50% – 50%)

32 contaminated. completed, and whenever surfaces are overtly are procedures all after use, to prior infected be properly cleaned, decontaminated and dis- should surfaces All locations. different in ple be performed successively or by different peo times.Preparation must cells radiolabelled of all at prevented be should blood of mix-up or contamination Cross environment. sterile workbench is not an alternative to a controlled an open or closed vial system on a laboratory ration of Radiopharmaceuticals [1]. The use of Radiopharmacy Practice (cGRPP) in the Prepa- follow the EANM guidelines on current Good should and conditions aseptic strict require cells of procedures radiolabelling and tions - Manipula radiolabelling. and manipulation cell during hazard radiation and biological to exposure operator’s the avoid to and ity - steril and viability cell both maintain to sary neces- is it application, clinical the of or used radionuclide the of cells, blood the of ture na- the of Regardless 1). (Table applications clinical varies for approaches radiolabelling and radionuclides different with diolabelled ra- be can elements cellular blood Several Tanja GmeinerStopar, PhD Blood Labelling Chapter 5–Radiopharmacy - 33 develop from committed stem cells through cells stem committed from develop bones.large of They marrow bone red the in Erythrocytes are continuously being produced tissues. body to lungs from livering de is function main cell. Their blood of type Red blood cells (RBCs) are the most common bloodcellsRed [1-3]. shouldbeperformed identity blue. Prior to administration, control of patient by use of suitable procedures i.e. using trypan ascertained be should cells the of integrity the intervals, regular At contamination. late clumping of cells and for presence of - particu of aggregation for checked be should blood calculated.cells) Before release, radiolabelled of ofradiolabelling (percentage efficiency radiolabelling and checked be should purity human use. Whenever possible radiochemical rials used should be identified and certified for dures should be followed at all times. All mate During radiolabelling, approved written proce marrow [4]. bone and spleen, the in destroyed are they subsequently and phagocytes by tion recognito susceptible it - making membrane undergoes erythrocyte changes in its plasma of aging The days. 120 about of total a live and erythrocytes mature to reticulocytes - - - EANM Table 1: Clinical applications of radiolabelled cells and radiolabelling approach

Radionuclide Radiolabelling Clinical application Blood cellular element /radiolabel approach

Cardiac and vascular In vivo Red cells 99mTc-pertechnetate imaging In vivo/in vitro

Gastrointestinal In vivo Red cells 99mTc-pertechnetate bleeding In vivo/in vitro

In vitro Spleen imaging Denaturated red cells 99mTc-pertechnetate In vivo/in vitro

Blood volume and red 99mTc-pertechnetate Red cells In vitro cell volume 51Cr-chromate

Red cell survival Red cells 51Cr-chromate In vitro

Site of Red cells 51Cr-chromate In vitro destruction

111In-oxine and White blood cells 111In-tropolone In vitro 99mTc-HMPAO

111In-oxine Abnormal platelet Platelets 111In-tropolone In vitro deposition 99mTc-HMPAO

34 vitro and combined in vivo/in vitro. The basic in vivo, in by may approaches Radiolabelling in lower labellingefficiency. brane such as heparin or hydralazine, resulting stannous ion transport through the cell mem- inhibit or interfere may which drugs taking are who patients in employed be also may It volume. blood and cell red of determination ble labelling over time. It may be used for the highest labelling andefficiency the most sta- vitroIn radiolabelling of RBCs gives by far the vitro radiolabelling In body weight. ling is in the range of 10-20μg per kilogram of stannous required for optimal radiolabel- pyrophosphate or medronate. The amount of as chelator,such weak a of complex a in ally and precipitation, stannous ions are thus usu- hydrolysis preventTo system. loendothelial rapidly removed from the blood by the reticu - are likely to hydrolyse and precipitate and are moglobin. At physiological pH, stannous ions subsequently binds to the beta chain of hae and cell presencethe the in ions stannous of reducedin becomes and membrane cell the nents. The pertechnetate diffuses freely across compo cellular to bound firmly are and cell the into diffuse ions stannous The cells. the before min 10-30 for ions stannous are “pre-tinned”by 99m mechanism of the radiolabelling of RBCs with with Radiolabelling Tc is in all approaches the same. The RBCs same. The the approaches all in Tcis 99m Tc-pertechnetate is added to added is Tc-pertechnetate 99m Tc - - 35 followed by injection of injection by followed is agent stannous of reconstitutedsolution a of injection An technique. radiolabelling ing consum- time least and simplest the is This vivo radiolabelling In before re-injection. cells are separated and re-suspended in saline centrifugation. and saline of fewmls Thea of unbound activity is washed away by addition utes with occasional mixing. After incubation, batedwith incu- and separated are cells Thetrifugation. cen- by removed be may and hypochlorite Sn of excess Any agent. stannous reconstituted or ACD)arin is incubated with an aliquot of a A small volume of anticoagulated blood (hep lower and more variable labelling efficiency. labelling variable more and lower generally a is approach radiolabelling this of disadvantage major later.The min 20-30 agent is followed by withdrawal of an aliquot the intravenous administration of a stannous belling approach are in use. In all approaches, More of variations the in vivo/in vitro radiola- vivo/in vitroIn radiolabelling and/or low haematocrit. sequence of low haemoglobin concentration activity. Low labelling yields may also be a con- cell membrane, resulting in a high background 99m 99m tion into the cells which results in reduction of This may be due to insufficient Sn Tc-pertechnetate outside the RBC. Reduced 2+ Tc is then not able to diffuse across the red is oxidised by addition of 0.1% sodium 0.1% of addition by oxidised is Chapter 5 – Radiopharmacy: Blood Labelling Blood Chapter 5–Radiopharmacy: 99m Tc-pertechnetatefor min- 5-20 99m Tc-pertechnetate 2+ - incorpora - EANM of pre-tinned blood 15-30 min after applica- Radiolabelling of RBCs can be affected by pa- tion. The excess of Sn2+ not incorporated into tient . Drugs may interfere directly cells may be removed by centrifugation before by reaction with Sn2+ by preventing accumula- 99mTc-pertechnetate is added to the cells. Al- tion of Sn2+ in the cells or indirectly by affect- ternatively blood may be taken into a shielded ing the RBC membrane or reducing the hae- syringe containing an anticoagulant and the matocrit and/or haemoglobin concentration. required amount of 99mTc-pertechnetate.The For more detailed information see [2,5-7]. blood is then mixed with the 99mTc-pertech- netate and allowed to incubate for 5-20 min at The usual administered activity of 99mTc-RBCs room temperature with occasional mixing. The for adult patients is within the range of 500 unbound activity is washed away by centrifu- – 1050 MBq. For children the activity may be gation before reinjection. Radiolabelled blood adjusted according to body weight, with a may alternatively also be re-injected without minimum activity of 80 MBq in order to ob- removal of unbound activity. With the later ap- tain images of sufficient quality [8]. Only when proach in which no washing step is involved in vivo radiolabelling approach is employed, one can expect lower radiolabelling efficiency breast feeding should be interrupted and the and higher background activity, depending expressed feeds discarded due to the pres- on the complexity (number of washing steps ence of free 99mTc-pertechnetate which con- avoided) of the procedure. centrates in the mammary gland. The total fractional activity ingested by the baby from in Heat-damaged RBCs vivo radiolabelled RBCs is estimated to be 3 – 5 When radiolabelled RBCs are damaged by times higher than the activity in milk from in heat, they will be recognised by phagocytes vitro radiolabelling. After in vitro radiolabelling and subsequently destroyed in the spleen, breast feeding can be continued [9]. liver and bone marrow. This mechanism en- ables the use of heat-damaged 99mTc-RBCs for General recommendations for application of spleen imaging studies. Radiolabelled RBCs radioactive drugs are applicable for adminis- are damaged by incubation in bath at tration of radiolabelled RBCs. Use of a teflon 49.5 °C for 15 min before reinjection. To suf- catheter or cannula should be avoided for ad- ficiently denature RBCs but prevent bursting ministration of Sn2+ compounds because Sn2+ them, the temperature and incubation time can react with the catheter [10]. To prevent are critical. Localisation in liver indicates pres- reaction of 99mTc-pertechnetate with traces ence of cell destruction formatting bursting of Sn2+ the stannous agent in the cannula fragments. and 99mTc-pertechnetate should not be given through the same system.

36 o ea lbn hi o te haemoglobin the of chain globin beta to Radiolabelling of Radiolabelling RBCs with in vitro: in taken place (after 30 min or longer if the pa- the if longer or min 30 (after place taken mixing of radiolabelled re-injected blood has calculations. dard for further completeWhen the patient and the other part is used as a stan- to injected is blood radiolabelled the of part For RBC mass and volume determination, one RBC massandvolume determination volume [2,11,12]. unknown the of calculation for base the is added tity ing (number of counts per mass) to the quan- The measured ratio of the quantity mix after counter). gamma a in (counted quantitated removedand then is mixture the of quantity labelled blood is allowed to mix, and a known unknown volume of blood in the body. Radio toadded is RBCs radiolabelled of an quantity using radiolabelled RBCs is the same: a known The basic principle in all non-imaging studies Non imaging studies washed away by centrifugation. to chromic ion. Alternatively, free chromate is which reduces the chromate outside the cells acid ascorbic adding by stopped is process labelling cell. The the in retained is molecule (Cr ion chromic to reduced is it where RBCs, the into diffuses freely ion ACD for approximately 10 -15 min. Chromate containing blood whole with incubated is with Radiolabelling 51 Cr in the form of sodium chromate sodium of form the in Cr 51 Cr 51 Cr is out carried 3+ . Cr ). 3+ bound - - 37 counted at the end of the study.Forthe the of end the at counted the need for decay correction, the samples are eliminateTo injection. after weeks 4 to 2 for week a times 3 obtained are samples blood 51 studies, sequestration and survival RBC For RBC survival volume. by dividing the red cell mass by the true blood The total body haematocrit can be calculated volume.plasma the redand the mass up cell summing by obtained then is volume blood lated by using the dilution equations. The true calcu- are volume plasma and mass cell red counter.The gamma a in counting for taken are samples blood splenomegaly), has tient the normal being 25 to 35 days. In case of a of case In days. 35 to 25 being normal the effective half-life is calculated from the curve, RBC patient’s The curve. the linearise to per pa- semilog a on plotted be can time over samples blood the of activity curve, survival sequestration studies. and survival for MBq 4.0 - 2.0 and MBq 1.5 – 0.8 is determination volume and mass RBC The usual administered activity of and heart. liver spleen, over positioning probe uptake 51 RBCs, like blood pool or liver, may be present. of site expected other the to relative uptake splenic in increase progressive and nificant significant splenic sequestration of RBCs, a sig- Cr-RBC uptake is monitored using using monitored is uptake Cr-RBC Cr-RBCs are reinjected to the patient and patient the to reinjected are Cr-RBCs Chapter 5 – Radiopharmacy: Blood Labelling Blood Chapter 5–Radiopharmacy: 51 Cr-RBC for 51 Cr EANM Leucocytes and platelets Neutral lipophilic complexes rapidly diffuse White blood cells (WBCs) or leukocytes are across cell membranes. Once inside the cell, cells of the immune system defending the the complex either dissociates and allows 111In body against both infectious and for- to bind to intracellular proteins (111In-oxine) or eign materials. Several different and diverse breaks down to a more hydrophilic complex types of WBC exist. They are all produced and which is unable to cross the cell membrane derived from a multipotent hematopoietic and is thus trapped in the cell (99mTc-HMPAO). stem cell in the bone marrow. WBCs are found In the case of radiolabelling with 111In-oxine, throughout the body, including the blood and 111In also binds to transferrin present in the lymphatic systems. One primary technique plasma. Therefore the cells have to be washed to classify WBCs is to look for the presence thoroughly to remove plasma before radiola- of granules, which allows the differentiation belling. In the case of radiolabelling with either of cells into two categories: granulocytes 111In-tropolone or 99mTc-HMPAO, radiolabel- (neutrophils, basophils and eosinophils) and ling can take place in the presence of small agranulocytes (lymphocytes, monocytes and amounts of plasma. macrophages) [4]. Because of the non-selective approach, the Platelets or thrombocytes are blood cells involved cells need to be separated prior to radiolabel- in the cellular mechanisms of primary haemosta- ling. The separation of WBCs and platelets from sis leading to the formation of blood clots [4]. RBC in the blood can be achieved by sedimen- tation of anticoagulated blood. 30-50 ml of Radiolabelling of WBCs and platelets blood is taken into a 60 ml syringe containing Non-selective lipophilic 111In and 99mTc complex- an anti-coagulant. The anti-coagulant of choice es, which label all cells indiscriminately are used is acid-citrate-dextrose (ACD) in concentration for radiolabelling of WBCs and platelets. Gen- 1.5 parts of ACD to 8.5 parts of whole blood. erally radiolabelling efficiency is higher when Erythrocyte sedimentation may be accelerated 111In complexes are used (80-90%) compared by the use of sedimentation agents such as to 99mTc-HMPAO, where radiolabelling efficiency 6% hydroxyethyl starch (Hespan). Alternatively is normally 50-80%. Availability, low radiation 6% dextran or methylcellulose may be used. exposure and better imaging characteristics are Normally 3 ml of Hespan per 30 ml of whole major advantages when 99mTc-HMPAO is used blood is used. Hespan may be added to ACD for radiolabelling. The clinical results using 111In in a syringe before blood is taken. Sedimenta- or 99mTc-HMPAO WBC are similar. However when tion time is generally 45-60 min and may be 99mTc is used for radiolabelling, scans can be affected by different factors such as number completed sooner, because imaging takes place of cells and certain disease states. Sedimenta- at 1 hour and at between 4-6 hours [2,12]. tion may be carried out in the syringe placed

38 - centrifuga additional an by achieved is This platelets. of separation for used be also may the removedfromWBCs plasma rich Platelet within3hoursofremoval.injected be should cells the and practical; as quickly as completed be should labelling the cells, radiolabelled of viability optimal ensure To e.g. 500-700g. rich plasma by centrifugation at higher speed diluted plasma. Plasma is prepared from plated re-suspended before re-injection with saline or away by centrifugation. Radiolabelled cells are saline; and free fraction of radiolabel is washed in re-suspended are cells the radiolabelling, when longer is it Generally used. agent radiolabelling the on depending varies time Incubation perature. tem- room at incubated is mixture RBCs.The pellet containing WBCs and small amounts of the to added is agent radiolabelling the fore e.g. 150 g. Platelet rich plasma is removed be speed low at spinned is plasma the platelets, from tube.To WBCs separate universal sterile taining WBCs and platelets is transferred into a tube. After sedimentation, the upper layer con- universal a in or holder suitable a in upward 99m Tc-HMPAO is used. After Tc-HMPAOused. is - 39 platelets is thesameasfor leucocytes. removed. The radiolabelling procedure of the be can plasma and pellet the in spinned are tion step at higher speed where the platelets into the cells is usually described as radiola- as described usually is cells the into The incorporated percentage of radioactivity efficiency Radiolabelling information see[2,5]. detailed therapy.Formore drug patient a by affected be could radiolabelling Cell [9]. ing when interrupted and the expressed feeds discarded sufficient quality [8]. Breast feeding should be of images obtain to order HMPAO-WBCsin of MBq 40 of activity minimum a with ity may be adjusted according to body weight, (range of 185-450 MBq). For children the - activ MBq; and for The recommended dose for Labelling efficiency isthencalculated: Labelling efficiency cells is measured before and after separation. labelled the of centrifugation. byactivity The cells are separated from the labelling medium suspended and the re-injected: radiolabelled beforestepare last re- cells the radiolabelled belling efficiency. It should be determined as Chapter 5 – Radiopharmacy: Blood Labelling Blood Chapter 5–Radiopharmacy: 99m Tc-HMPAO-WBCs is used for imag- for Tc-HMPAO-WBCsused is 99m Tc-HMPAO-WBCs, it is 400 MBq 111 In-WBCs In-WBCs is 18.5 99m Tc- EANM Nevertheless a high radiolabelling efficiency is not necessarily indicative of a good labelling procedure or viable cells. Regardless of the ra- diolabelling efficiency, it is important to obtain a viable population of cells for reinjection.

Cell viability It is essential that radiolabelled cells remain viable when they are re-injected to the body. They may be damaged from the harvesting and/or radiolabelling procedures. Cell viability is most frequently assessed by Trypan blue exclusion assay. Trypan blue is a stain which is incorporated into dead cells, whereas live cells are not coloured. Equal volumes (0.1 – 0.2 ml) of radiolabelled cell suspension and 0.4% Try- pan blue are gently mixed in an appropriate tube and incubated at room temperature for 5 minutes. The mixture is applied on a haemocy- tometer slide and cells counted under a light microscope. The percentage of viable cells is the number of viable cells divided by the number of dead and viable cells. Usually it should be >95%.

40 tion ofpatients. Directive) lays down provisions for the protec- Exposures (Medical 97/43/Euratom Directive protection ofpersonnel. the for provisions down lays Directive) dard Stan- Safety (Basic 96/29/Euratom Directive (GMP) for Products Medicinal for humanuse. the principles of Good Manufacturing Practice details (1991) 91/356/EEC Directive Council Current legislative framework and 84/467/Euratom (staffandpublic). of the provisions of 84/466/Euratom (patients) incorporation the to regard with particularly 83/570/EEC Directive Council and 87/21/EEC Councilboth Directiveof scope the extended 1989, in issued 89/343/EEC Directive Council visions laiddown for radiopharmaceuticals. tives respectively with regard to additional pro tive 83/570/EEC amended the two above Direc- Council Directive 87/21/EEC and Council Direc- radiopharmaceuticals. these of marketing and manufacturing the authorising for conditions the and ceuticals - radiopharma of market the on placing the Council Directive 75/319/EEC (1975) dealt with administration to patients. of purpose the for thereof pharmaceuticals age and elution and the production of radio the use of radionuclide generators, their stor Council Directive 65/65/EEC (1965) dealt with Historical legislative framework Brendan McCoubrey andAdministrationRecord Keeping Chapter 6–Radiopharmacy - - - 41 The principal concerns of existing legislation existing of concerns principal The Legislative rationale be assessed initially and reviewed regularly by vidual. Ability and competence of staff should indi- the by performed tasks the topropriate the radiopharmacy. The training should be ap to play in ongoing radiation protection within procedures in the facility. This has a large part documented the and practices working the petence of the staff in the implementation of Training of personnel: The professional com - standards.radiopharmaceutical pliance with the relevant legislation regarding the radiopharmacy to ensure continued com- within monitoring equipment of and testing control quality of frequencies and standards of implementation The Assurance: Quality record anddocumentationare: keeping and guidelines with regard to radiopharmacy as provided for under the terms of the licence. substances radioactive of manipulation each of the holder’s licence, records must be kept of terms the Under disposal. waste subsequent all radioactive products and material, and their Records of waste disposal: the facility. from service dispensing the relevant, where and facility the to radionuclides of transport transport of radioactive material. This includes Transport: cord ofcompletion shouldbemaintained. re a and process training the of description detailed A facility. the managing person the The packaging, movement, and movement, packaging, The Waste storage of - - EANM Therefore, the record must identify the date e) Details of where and how radionuclides are of acquisition of all unsealed radioactive sub- handled. stances, their radioactive content then and at f) Routine monitoring procedures. the subsequent time of disposal, along with g) Records to be kept. the date and method of disposal. For sealed h) Action to be taken in the event of a spill. radioactive sources, a record must be kept, i) Date when local rules were drawn up / detailing acquisition date, source classifica- superseded. tion, results of wipe tests and the method and date of disposal. When radioactive waste has Record keeping and documentation decayed and is ready for final disposal all radio- The keeping of adequate records is a stan- active warning signs must be removed. dard requirement of a radiopharmacy to ensure continued good radiopharmacy Environmental and microbiological monitor- practice. These records may be classified ing: Adequate environmental and microbiological according to the following main areas of monitoring procedures are a requirement of Good responsibility. Manufacturing Practice (GMP). This necessitates regular adherence to a suitable protocol of testing • Patient medical examinations of environmental and microbiological standards • Calibration and testing of monitors with set warning and action limits and the keep- • Maintenance of equipment ing of documented records of compliance. • Inventory of sources and equipment • Movement of sources and equipment Local rules • Source material accounting, including re- These should contain clearly defined proce- ceipt and disposal details dures for working with radioactive materials • Leak tests and area monitoring and should include: • Staff • Accidental or emergency exposure a) Names of those on the Hospital Radiation Safety Committee. Specifically these records pertain to the continued b) Specification of controlled and supervised optimised operation of all areas within the radiop- areas. harmacy and should provide systematic retrospec- c) Systems of work for controlled areas. tive evidence that each area continues to meet d) Details of storage of radionuclides. performance criteria laid down by both legislation and guidelines at national and European levels.

42 be regularly monitored. also must techniques Operator appropriate. where standards suitable against calibrated and checks performance regular to subject established standards. All equipment must be radioactive contamination levels comply with to ensure that microbiological, particulate and ing environment must be suitably monitored be maintained and kept up to date. The work to written procedures. Accurate records must spectively achieved through strict adherence orously test before administration. QA is retro Due to half-livesshort it is not possible to - rig assuranceQuality documentation maceuticals administered to patients. source, composition and activity of all radiophar is essential so that it will be possible to trace the facilities. Accurate and complete record keeping suitable and sufficient premises, equipment and equately resourced with competent personnel, the Quality Assurance (QA) system should be ad- of aspects All monitored. effectiveness its and must be in place. It should be fully documented Control(QC), Quality and (GMP) Practice turing Quality Assurance, incorporating Good - Manufac designed and correctly implemented system a comprehensively of this, achieve efficacy. To or patients at risk due to inadequate safety, quality keting authorisation, and that they do not place they comply with the requirements of the mar ensure that they are fit for their intended use, that mustmanufacture medicinal products so as to authorisation manufacturing a of holder The documentation Healthcare management quality Chapter 6 – Radiopharmacy: Record KeepingChapter 6–Radiopharmacy: andAdministration - - - - 43 or administration of radiopharmaceuticals radiopharmaceuticals of administration or preparation the involving incidents Adverse actions to administered radiopharmaceuticals. products andforofadverse re thereporting defective possible of reporting the for bases Data- European central two established has The European Association of Nuclear Medicine scheme EANM reporting adequately traced. be can preparation each of history the that such operation in be must documentation of system A delivery. final to up and source should be capable of tracing all materials from records These correctness. for checked and documented be should facility the by terials individual patient doses. The receipt of all ma- of administration the to extend should trail audit the and radiopharmaceuticals; as use for materials of purchase the with originate should documentation Assurance Quality pharmacy pharmacy facility into its component elements. radio the of operation the separate first to necessary is it process, documentation and recording systematic complete a ensureTo documentation Inventory records ofradiopharmacy and harmacy/adverse_reactions.pdf http://www.eanm.org/committees/radiop 2002 EANM Adverse Report Reactions EANM website isprovided below. the to link A EANM. the to forwarded be also thority in the first instance; and details should au- local relevant the to notified be should - ­ -

EANM A detailed Standard Operating Policy (SOP) Radiopharmaceutical reconstitution records concerning record keeping and documenta- • Name of the preparation tion should be drawn up for each of the fol- • Route of administration lowing areas, specifically listing the required • Activity in Becquerel’s data fields to be completed for each separate • Volume operation within the radiopharmacy. • Time / Date measured • Batch no. General radiopharmacy operative records • Radiation warning trefoil • Standard Operation Protocols (SOPs) • Applicable special storage conditions • Records of workstation performance • Expiry date • Records of microbial and particulate levels • Applicable special preparatory in the lab and workstation instructions • Data on starting materials and • Address of radiopharmacy ingredients • Transport index of the packaged product • Data on the production process • Personnel at all stages • Data on distribution of the final product to allow recall or halting Gamma Camera/s Records • Disposal of radioactive waste • Date • Emergency procedures • Personnel • Risk assessment forms • Camera peaking • Minor / major spill incident forms • Peaked • Window Radiopharmacy generator/s records • Dead time • Date • Co57 flood source • Generator lot no. • % UFOV result • Generator expiry • % CFOV result • Elution activity • Ionisation chamber • Elution time • Constancy test Cs137 • Elution volume • Calibration test Tc99m • Mo breakthrough test • Ionisation chamber self test • Radiopharmaceutical lot no. • Radiopharmaceutical expiry Patient Records • Reconstitution time • Patient name • Reconstitution volume • no. • Reconstitution activity • Patient source • Personnel at all stages • Consent

44 • • recordsNational authority • • • • recordsPersonnel dosimetry • • • • statistics Workload • • • • • • • • • • • • • • Suppliers’External Records Certificates ofcompliance: Certificates Correspondence Background readings Contamination levels readings Extremity Personnel readings Demographics Sedation GA Exam type Patient incidentforms Administrator route Administrator Time ofinjection Activity expiry Radiopharmaceutical kit Radiopharmaceutical Radiographer Date ofexam Examination no. Examination type Kit ordering Kit andlogbooks Repairs Manuals • • • • Dose rateDose meter Contamination monitor calibratorDose Camera Chapter 6 – Radiopharmacy: Record KeepingChapter 6–Radiopharmacy: andAdministration 45 In In accordance with GMP, procedures must be Release orfailure ofpreparations • • • • Internal records hospital supply • • • tory test results are obtained after dispatch. after obtained are results test tory unsatisfac- if facility the by taken be to sures The procedure should also describe the mea- dispatched. is batch the before reviewed be should which data, control quality and tion produc- all detailing procedure written a be should there authorisation, manufacturing a to release/failure assessment. For the holder of put in place whereby a final product is subject c) b) a) include: should preparations of release/failure the for Conditionstime. of space short a within able Recall operations should be shown to be oper

A written releaseA written procedure, effected onlyif: taken by an authorised person prior to prior person authorised an by taken approval of decision recorded formal A Technical services CSSD Stores Pharmacy upgrades Software Accessories Generator ordering anddelivery fect where a failure to meet the required the meet to failure a where fect release ofpreparations. ii) i) A written procedure which should take ef- specifications. The product complies with the release accordance withGMP; The producthasbeenprepared in - EANM standard is recorded. The event should be External Transport of Radioactive documented and investigated. Materials d) A written procedure should exist for the Packages for external transport from the recall of defective radiopharmaceuticals. radiopharmacy must be labelled with the correct international transport labels show- Transport of Radioactive Materials ing the radionuclide, activity and transport All of the regulations and codes of practice index. Criteria for these labels are strictly pre- covering the transport of radioactive material scribed by the IAEA. Figure 1 gives an example are based on the safety standard publications of the criteria pertaining to the dimensions of the IAEA. Responsibility for transport must and ratios of radiation warning labels. Figure be clearly allocated; and adequate records 2 demonstrates the criteria for the classifica- of dispatch and receipt should be kept. All tion of packages. Figure 3 gives an example containers should be suitably labelled; and of a Category II package warning label. Trans- these labels should be removed from empty port documents must also be completed as containers. Procedures for transport should required by national legislation. be laid down in the Local Rules. These should take account of any hazardous situations that may arise during transport and of detailed pro- cedures for dealing with those. Links to the International Atomic Energy Agency (IAEA) Transport Regulations 2005 may be found on the following websites:

• The International Atomic Energy Agency (IAEA) Regulations for the Safe Transport of Radioactive Material: http://www.iaea. org/

• Information Sheet at World Nuclear Trans- port Institute http://www.wnti.co.uk/User- Files/File/public/publications/factsheets/ wnti_fs-2.pdf

46 overpacks (1). Figure and 2:Categories ofpackages shall be4mm(1). radius X. The minimumallowable size ofX basedonacentralcircle of proportions Figure 1:Basictrefoil symbolwith Chapter 6 – Radiopharmacy: Record KeepingChapter 6–Radiopharmacy: andAdministration 47 barsshallbered (1). category andthecolourof shallbeblack, printing half white, thecolouroftrefoil andthe the labelshallbeyellow andthelower background colouroftheupperhalf Figure II 3:Category Yellow Label. The possible or in clear, legible indelible handwrit where computerised be should entries All Process for thecreation ofrecords should be encrypted in accordance with Na- accordancewith in encrypted be should data Sensitive location. secure separate a at stored and regularly up backed be should Data employed. be should codes or words authorised access by means of individual pass- systems are utilised for the creation of records, computerised Where laws. data national to according retained be should record the in son for the alteration where relevant. The data record should be signed and dated with a rea- the to Alterations action. the for responsible person the by taken is action each time the tory. Record keeping should be completed at ing. The use of block letters should be manda- - EANM tional Data Protection legislation. Alternative arrangements should be in place in the event of a breakdown; and these temporary records should be incorporated into the permanent log as soon as possible after the re-establish- ment of normal service.

Control of documents A Master Document should be created and the number and location of approved copies recorded. Every document should contain a version number and a review date. A system should be in place to prevent the inadvertent use of superseded documents.

48 rent Radiopharmacy Good Medicine. 3 1. Chapter 4 Accessed: 01Aug 2008. lines/gl_radioph_cgrpp.pdf . at: Available Medicine. 2007. Nuclear in Radiopharmaceuticals for (cGRPP) Practices 3. Accessed: 01Aug 2008. vol-4/pdfs-m/2006_10_10_annex3_consultation.pdf . http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/ 2006. acture ofRadiopharmaceuticals. - Manuf 3: Annex Use. Veterinary and Human for Products Medicinal Practice: Manufacturing Good to Guidelines EU the European Union. Vol 4. 2. Accessed: 01Aug 2008. doc/legislation/9629_en.pdf . http://ec.europa.eu/energy/nuclear/radioprotection/ 1. Chapter 2 New York, USA:Springer Verlag; 2003. 4. 26. Uppsala,Sweden: NLNPublications; 1989. ration and control of radiopharmaceuticals in hospitals. No 3. cesses. New York, USA:John Wiley 2008.59-96. &Sons; Pharmaceutical Manufacturing Handbook; Production and Pro 2. 153-180. for the 1990’s. Buffalo Grove,Il, USA:Interpharm Press; 1995. cals. Aseptic Pharmaceutical II; Manufacturing Application 1. Chapter 1 References

EANM Radiopharmacy Committee. Guidelines EANM on Radiopharmacy Cur Prepa- Radiopharmacy: Medicines. on Council Nordic - Radiopharmaceuti of ProductionO.Aseptic P Bremer Eudralex: The Rules Governing Medicinal Products in Products Medicinal Governing Rules The Eudralex: Farstad B S, Peñuelas I. Radiopharmaceutical manufacturing. EURATOM. European Council Directive 96/29/EURATO. 1996. Sharp P F, Gemmel H G, Smith F W. Practical Nuclear Practical W.F Smith G, H F, Gemmel P Sharp Saha G B. Fundamentals of . 5 Pharmacy. Nuclear of Fundamentals B. G Saha rd rd http://www.eanm.org/scientific_info/guide Ed. Oxford, Press; University 2005. UK: th Ed. Ed. - - - 49 Analyzer. 1963;August; 158(2):309–318. AnnalsofSurgery Cessation of Breast Feeding. Applying Radiation Safety Standards 8. 10.1007/s00259-008-0799-9. DOI 2008;35: Imaging Molecular and Medicine Nuclear of new “The EANM paediatric dosage card. ” European Journal 7. 1983;24:397–401. Blood Cells. ofNuclearMedicine Journal nication: Pharmacologic Alterations in Tc-99m Binding by Red 6. DrugSafety 1993;8:280–94. with Radiopharmaceuticals. 5. 4 4. nications 1996;17:648-58. labelling Blood Cells: A Review. Nuclear Medicine Commu - 3. – Asafe andeffective approach. IAEApublicationinpress. 2. and Practice. 3 Theory Radiopharmacy of Textbook practice. and theory 1. Chapter 5 Mass Mass and Plasma Volume with Cr 10. 1983;8:502-4. of NuclearMedicine Cannulae and Stannous Pyrophosphate. European Journal Red Blood Cells with 9. No40.2005:97–9. Series. in NuclearMedicine. Safety Reports (as ofAugust 1,2008).2005. publications/PDF/Pub1225_web.pdf Environment. Available at: the and People Protecting for Standards Safety Material. Radioactive of Transport Safe the for Regulations IAEA. Chapter 6 USA: Lippincott-Raven Publishers; 1998. 11. Breach Publishers; Science 1999.p. 83-104. th

Ed. St.Louis: Mosby, St.Louis: Inc. Mosby, 1998.319-324. Inc.;

International Atomic Energy Agency (IAEA). Appendix IV: IV: Appendix (IAEA). Agency Energy Atomic International Wilson M A. Textbook of Nuclear Medicine. Philadelphia, Solanki Solanki K K. Operational guidance on hospital radiopharmacy Berne Berne R M, Levy M N, Koeppen B M, Stanton B A. Physiology. Sampson C B. Adverse Reactions and Drug Interactions Lassmann M, Biassoni L, Monsieurs M, Franzius C et al. et FranziusC M, Monsieurs L, Biassoni M, Lassmann Radio in Difficulties and Complications B. C Sampson – cells blood of Radiolabelling B. C Sampson L, B Ellis Millar A Millar M, Wathen C G, Muir A L. Failure in Labelling of Karlson Karlson K E, Senn L Y. Simultaneous Determination of Red Cell Lee H B, Wexler J P, Scharf S C, Blaufox M D. Concise Commu- rd Ed. Amsterdam, Netherlands: Gordon and 99m Tc: Interaction between Intravenous http://www-pub.iaea.org/MTCD/ 51 and I 131 Using a Pulse Height - EANM Imprint

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