**An Overview of PET Radiopharmaceuticals in Clinical Use: Regulatory, Quality and Pharmacopeia Monographs of the United States and Europe**

Ya-Yao Huang

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.79227

#### **Abstract**

Since 1976, more and more PET radiopharmaceuticals have been developed as the clinical introduction of [18F]FDG for various medical applications. However, few of them could be involved in routinely clinical use in hospitals partly because of restrictions in regulatory and facilities. This chapter aims to provide an overview of PET radiopharmaceuticals that are common manufactured (or prepared) in industry (or hospitals) about regulatory and quality aspects, and further summarize pharmacopeia-listed PET radiopharmaceuticals and their clinical usefulness herein. Particularly, PET radiopharmaceuticals listed in latest United States Pharmacopeia (USP) and/or European Pharmacopeia (EP) are included for this chapter. Finally, this chapter would be helpful in the basic understanding of clinical PET radiopharmaceuticals for physicians or technologists.

**Keywords:** PET, radiopharmaceutical, regulation, quality, clinical application, USP, EP, pharmacopeia

#### **1. Introduction**

 Positron emission tomography (PET) radiopharmaceutical is composed of a biologically active pharmacophore and a positron-emitting radionuclide, and belongs to a unique species in pharmaceutical field. The most common radionuclides for PET radiopharmaceuticals include 11C, 15O, 13N, 18F, 68Ga and 82Rb (**Table 1**). In addition to radiation issue, short halflives of these positron emitters (78sec~110min) definitely result in unavoidable limitations on manufacturing (including production and following quality control (QC) analyses) and clinical use of PET radiopharmaceuticals. Above are all practical challenges for a conventional

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


**Table 1.** Characteristics of common positron emitters.-

pharmaceutical industry. Hence, commercial large-scale manufacturing and small-scale preparation of PET radiopharmaceuticals are respectively allowed in radiopharmaceutical industries and the radiopharmacy of hospitals in most countries worldwide. Moreover, both practices in radiopharmaceutical industries and hospitals are clearly regulated by national competence authorities, such as Food and Drug Administration (FDA) of the United States (U.S.) and *European* Medicines Agency (EMA) of the European Union (EU).

In the other hand, a pharmacopeia is a national compendium of drug quality standards, such as U.S. Pharmacopeia (USP) and European Pharmacopeia (EP), and is always recognized as an official compendium. Drug standards listed in pharmacopeia monographs are usually enforced to be compliance under drug-related provisions at national level in order to prevent the marketing of inconsistent drugs and to reduce possible risks in public health. Although PET radiopharmaceuticals listing in pharmacopeia monographs sometimes do not mean for marketing authorization under national approval and reimbursement decision of medical insurance [1], some countries have enabled the clinical use (i.e., use for routine patient care with/without reimbursement or with/without national approval) or clinical trials as long as their qualities are in conformity with USP or EP standards, even no good manufacturing practice (*GMP*)-compliant process. Moreover, for those clinical studies using national-approved PET radiopharmaceutical for off-label indications, burdensome submission of an investigational new drug (IND) application will not be required in some countries.

In the other hand, specific QC procedures and specification of some PET radiopharmaceuticals have been listed in USP or EP. However, because of short half-lives of PET radiopharmaceuticals, QC tests prior to human administration within such a short period is a huge challenge. As a result, some quality exceptions are usually allowed for PET radiopharmaceuticals. Also, several efficient and quick tests have been developed for rapid QC tests of clinical PET radiopharmaceuticals.

This chapter first aims to provide an overview of regulations of manufacturing and clinical use of PET radiopharmaceuticals in U.S. and Europe. Secondly, the chapter will introduce the general quality aspect for PET radiopharmaceuticals. Finally, this chapter will end with the brief introduction of PET radiopharmaceuticals listed in the monographs of latest USP (USP 40) or EP (EP 9.0) (**Table 2**).

An Overview of PET Radiopharmaceuticals in Clinical Use: Regulatory, Quality and Pharmacopeia Monographs… 37 http://dx.doi.org/10.5772/intechopen.79227


\*These monographs of 8 FDA-unapproved PET radiopharmaceuticals have been omitted from USP since May 1, 2015 (USP 38).

**Table 2.** PET radiopharmaceuticals listed in USP and EP.

#### **2. Regulatory aspects of PET radiopharmaceuticals in the USA and Europe**

#### **2.1. USA regulatory view-**

In U.S., the clinical use of all radiopharmaceuticals has been regulated by FDA since 1975. Briefly, the regulatory process can be divided into two types. They are: 1. IND submission for investigational and research purposes by an individual or a commercial manufacturer, and 2. submissions of Notice of Claimed Investigational Exemption (NCIE), an abbreviated new drug application (ANDA) or New Drug Application (NDA) for commercial marketing only by a commercial manufacturer. However, because of the increasing clinical need of PET radiopharmaceuticals, based on FDA Modernization Act (FDAMA) in 1997 [2], PET radiopharmaceuticals were first categorized as positron-emitting drugs. In the same time, all PET radiopharmaceutical manufacturing facilities in U.S. were programmatically to compliant with PET drug GMP-compliance guideline or with USP General Chapter <823> [3], and further registered as manufacturers. Till now, these legal manufacturers could on-site *(in-house)*  produced PET radiopharmaceuticals with same specifications listed in USP monographs.-

In the other hand, USP is annually published by a nonprofit organization since 1820, U.S. Pharmacopeial Convention, and such organization also worked with FDA and specialists in academia and companies to establish monographs or general chapters. Typically, USP monographs are typically developed after FDA approval of the drug product for commercial marketing and thus a USP monograph of an FDA-approved drug has been used as one basis for a reimbursement decision. The first USP monograph for a PET drug was published in 1990 [4] and it described the quality specification and analytic methods for [18F]FDG injection. However, there had been an exception for 4 approved and 8 unapproved PET drugs listed in USP monographs till 2013. Moreover, not only these 12 monographs were provided to U.S. Pharmacopeial Convention by various academic sponsors with un-validated data and outdated analytic methods, but also these unapproved 8 PET drugs have limited commercial application without FDA-approved NDA or ANDA. Consequently, based on recommendations of the Society of Nuclear Medicine and Molecular Imaging (SNMMI) Committee [1], U.S. Pharmacopeial Convention announced the omission of the monographs of 8 unapproved PET drugs on June 2014 and the omission initiative became official on December 1, 2014.-

#### **2.2. European regulatory view-**

In Europe, radiopharmaceuticals have been recognized as a special group of medicines. Thus, the preparation and clinical use of PET radiopharmaceuticals have been regulated and variously adopted by member states. Similar to USP, EP has legal status in Europe. Compared to the USA, EP is only for drug quality and is independent of licensing status or clinical utility of such drug. Regarding to PET radiopharmaceuticals, corresponding monographs are elaborated by a group that is composed of academic, commercial and regulatory specialists. From another point of view, a number of EU member states have set up a regulatory framework from the definitions of "magistral and officinal formulae" that is listed in Article 3 of Directive 2001/83 [5]. Additionally, "in-house" small-scale preparation of PET radiopharmaceuticals is allowed without the requirements of a marketing authorization based on various national laws of European countries [5]. Both a general chapter of EP entitled "Extemporaneous Preparation of Radiopharmaceuticals" [6] and the new PIC/S guidance document with Annex 3 on radiopharmaceuticals [7] are published and worked as comprehensive guidelines for such magistral approach. Furthermore, because of the special characteristics of PET radiopharmaceuticals, the clinical studies using diagnostic radiopharmaceuticals do not fall within the GMP-compliance regulations of conventional drugs from EU Regulation no 536/2014 of 16 April 2014 [8, 9]. On brief summary, no matter EP or PIC/S document, they both clearly define a clear distinction between PET radiopharmaceuticals and conventional medicine, and further provide the corresponding guidance. All would be significantly helpful and powerful in promotion and development of PET radiopharmaceuticals in Europe.

## **3. Quality aspects of PET radiopharmaceuticals**

Even costly implementation and maintenance of quality system for a PET radiopharmaceutical manufacturing (or preparing) site [10, 11], it is still thought to be cost-effective [12]. Moreover, it will be helpful for qualified patient care, regulatory requirements, optimization of safety and efficacy for patient care and a reliable quantitative performance in both diagnostic and therapeutic nuclear medicine procedures [13]. Therefore, GMP-compliant PET manufacturing (or preparing) process including production, QC, quality assurance (QA), package and distribution has been required by competent authorities in many countries worldwide. Furthermore, during these years, the concept of "Quality by Design (QbD)" based on guidelines of International Conference on Harmonization (ICH) (ICH Q8 [14], ICH Q9 [15], and ICH Q10 [16]) has been the fundamental topic in pharmaceutical field and an appropriate quality system has been widely required to implement in many radiopharmaceutical manufacturing sites (**Figure 1**). Briefly, QA covers whole process and GMP specifically characterizes those production and QC activities that guarantee products are produced under the constant scrutiny of quality standards [17], although the association of QA, GMP, and QC throughout whole pharmaceutical process is slightly different in various guidelines.-

**Figure 1.** The inter-relationship for whole quality system in PET radiopharmaceutical manufacturing.

Particularly, QC procedure of PET radiopharmaceutical is usually critical and essential, since it is synthesized every day or is small-scale "prepared "in radiopharmacy of a hospital. A typical QC programme of a PET radiopharmaceutical is involved from radionuclide production to final product release and a series of QC tests for PET radiopharmaceuticals basically include:-


However, because of short-lives of PET radiopharmaceuticals, some lengthy tests cannot be performed prior to release for human use and are allowable to perform within a short time after the release. Furthermore, in addition to the limited time for QC of PET radiopharmaceuticals, limited personneal for *in-house* preparing of PET radiopharmaceuticals is another major issue for a hospital. Therefore, more and more efficient systems have been developed- and successfully implemented for clinical use, such as Endosafe® Portable Testing System™ (PTS™) for rapid endotoxin testing (Charles River, Wilmington, MA) (https://www.criver.- com/products-services/qc-microbial-solutions/endotoxin-testing/endotoxin-testing-systems/ endosafe-nexgen-pts?region=3681) and Tracer-QC system for automation of QC tests of PET radiopharmaceuticals (LabLogic Systems Ltd., Sheffield, UK) (https://lablogic.com/- nuclear-medicine-and-pet/instruments/tracer-qc).

#### **4. Overview of current PET radiopharmaceuticals listed in USP or EP-**

#### **4.1. [11C-methyl]Methionine injection (EP)**

Cellular protein synthesis is a well-control process for enzymes, membrane receptors, structural proteins, and growth factors [18]. Most importantly, increased cellular protein synthesis is often characterized in malignant growth [19]. Otherwise, decreased protein synthesis is found in certain neurodegenerative disorders [20]. Thus, the ability to *in vivo* visualize the protein synthesis rate is critical for clinic. Protein synthesis is initiated universally with the amino acid, methionine [21]. Therefore, one of 11C-labeled methionine analogs, [11C-methyl] methionine ([11C]MET) [22] (**Figure 2**), has been used for imaging of rate of protein synthesis [23, 24], although the short physical half-life of 11C (20min) limits its accessibility for- PET scanning centers without a cyclotron. Clinically, [11C]MET has been used in imaging of brain, urinary, gynecological, liver and lung cancer [25–28]. Particularly, the enhanced transport of [11C]MET into the brain has been known via the reversible sodium-independent transport system L (LAT 1) since 1995 [28] and increased LAT1 expression has been found in glioma and many other cancers and is associated with high grade and poor prognosis [29–32], thus [11C]MET has been widely in various brain tumors [33, 34].

#### **4.2. N-[11C-methyl]Flumazenil injection (EP)**

The GABAA/benzodiazepine receptor complex is also known as the central benzodiazepine receptor and specifically mediates all pharmacologic properties of ethanol, zinc, picrotoxin and some drugs such as benzodiazepines (sedative, anxiolytic, anticonvulsant, myorelaxant), An Overview of PET Radiopharmaceuticals in Clinical Use: Regulatory, Quality and Pharmacopeia Monographs… 41 http://dx.doi.org/10.5772/intechopen.79227

**Figure 2.** Chemical structures of PET radiopharmaceuticals listed in this chapter.

barbiturates (cerebral protection) and neuroactive steroids [35]. Based on a benzodiazepine antagonist, N-[11C-methyl]Flumazenil ([11C]FMZ) (**Figure 2**) [36] has been developed and known for its excellent kinetic properties for the image quantification [37]. Moreover, [11C] FMZ has been considered as a versatile PET tracer for assessment of several conditions, such as neuronal damage in head injury [38], epilepsy [39], stroke-induced penumbral areas of infarction [40] and Alzheimer's disease (AD) [41].

#### **4.3. [11C-methoxy]Raclopride injection (EP)**

Dopamine (DA) plays an important role in every-day brain functions including experiencing pleasure, regulating attention, and learning to control urges. Dysfunction of DA circuits has been thought to be related to various psychiatric diseases such as Parkinson's diseases (PD), addiction, attention-deficit hyperactivity disorder, and schizophrenia [42]. Studying *in vivo*  dopamine function in humans became possible in the mid-1990s with the development of [11C]raclopride (**Figure 2**) [43, 44], which originates from a DA receptor antagonist (D2 /D3 ) with moderate affinity and reversible binding characteristics. Up to now, [11C]raclopride is the most widely used PET radiopharmaceutical for measuring DA changes in striatal dopamine levels in the synapse before and after pharmacological and behavioral challenges [45], such as aging [46–48], schizophrenia [49–53] and PD [54, 55].

#### **4.4. [1-11C]sodium acetate injection (EP)**

Acetate is a molecule quickly picked-up by cells to convert into acetyl-CoA by acetyl-CoA synthetase (EC 6.2.1.1 according to Enzyme Commission Number) and participates in cytoplasmic lipid synthesis, which is believed to be increased in tumors. Thus, [1-11C] Sodium Acetate ([11C]Ac) (**Figure 2**) [56, 57] has been proved clinical usefulness in prostate cancer (PC) [58], hepatocellular carcinoma (HCC), lung cancer, nasopharyngeal carcinoma [33], renal cell carcinoma, bladder carcinoma and brain tumors [59]. Furthermore, [11C]Ac has been used to clinically measure myocardial oxygen consumption since 2010 [60] and used in some rare conditions, such as thymoma, cerebellopontine angle schwannoma, angiomyolipoma of the kidney, encephalitis, and multiple myeloma [59].

#### **4.5. [13N]NH3 injection (USP and EP)**

Coronary flow reserve (CFR) is calculated as the ratio of hyperemic to rest absolute myocardial blood flow (MBF) and is a particularly useful parameter in the assessment of adverse cardiovascular events such as epicardial coronary stenosis, diffuse atherosclerosis, and microvascular dysfunction on myocardial tissue perfusion [61]. Routinely used [13N]Ammonia ([13N]NH3 ) is not only a useful 13N-labeled PET imaging agent for assessing regional blood flow in tissues [62], but a well-validated radiotracer for clinical management of patients with coronary artery disease [62–64]. Moreover, recently [13N]NH3 has been used in PC, because the up-regulation of NH3 during *de novo* glutamine synthesis was known in tumors [65]. Furthermore, because excess circulating NH3 is neurotoxic and hyperammonemia is thought to be a major factor in the encephalopathy associated with several diseases, such as liver cirrhosis [66–68], [13N]NH3 is also used for elucidation of NH3 metabolism in patients with hepatic encephalopathy [69].

#### **4.6. [15O]CO injection (EP)**

[15O]CO is one of the most common tracers used for noninvasively measuring oxygen consumption and blood volume [70, 71]. Additionally, [15O]CO is crucial for the evaluation of acute stroke patients. Moreover, measurement of myocardial oxygen consumption is a useful tool to clarify the relationship between MBF and oxygen extraction fraction (OEF), because both OEF and MBF are important indicators in describing myocardial function [72].

#### **4.7. [15O]H2 O injection (EP)**

Although the short half-life (123 sec) of 15O results in the challenges in clinical use, [15O]H2 O is still the preferred tracer because of its ease production from generator, effectiveness and safety for- patient use [73]. Particularly, PET with [15O]H2 O has been a standard method and most reliable approach for quantitative measurement of cerebral blood *flow* (*CBF*). Also, [15O]H2 O is capable to clinically investigate cerebral and myocardial perfusion [74], and tumor perfusion [75, 76].

#### **4.8. [18F]FCH injection (EP)**

Choline is a precursor for the biosynthesis of phospholipids which are essential components of all membranes and is phosphorylated by choline kinase (CK) to produce phosphatidylcholine. Upregulated CK is known in cancer cells, thus it further leads to increased uptake of choline in tumor cells with the excess need for phospholipid biosynthesis [77, 78]. Consequently, 18F-labeled choline analogs, [18F]fluoromethylcholine ([18F]FCH) (**Figure 2**) [79, 80] has been a promising tumor imaging agents for various types of tumors include brain [80], breast, thyroid, lung, liver and prostate [81]. Particularly, [18F]FCH has been shown to be better than [18F]FDG for PC and HCC detections [81].

#### **4.9. [18F]FDG injection (USP and EP)**

Since its synthesis in 1976, 2-fluorine-[<sup>18</sup>F]fluorodeoxyglucose ([18F]FDG) [82] (**Figure 2**) has been the most widely used radiotracer for PET studies in neuroscience, cardiology and oncology (**Table 3**) [83]. After FDA approval in 1997, [18F]FDG with PET or PET/CT scanner became an established imaging tool in the clinical assessment of many neoplasms, as well as the nonmalignant diseases including dementia, myocardial ischaemia, inflammation and infection [84].

#### **4.10. [18F]FDOPA (prepared by electrophilic substitution) injection (EP)**

Dihydroxyphenylalanine (DOPA) has been known as an intermediate in the catecholamine synthesis pathway. One of the 18F-radiolabeled analogs, 3,4-dihydroxy-6-[18F]fluoro-*L*-phenylalanine ([18F]FDOPA) (**Figure 2**), was first reported as a PET tracer for imaging- pre-synaptic dopaminergic functions in 1983 [85]. Subsequent studies revealed the utility of [18F]FDOPA for the visualization of various peripheral tumor entities via PET [86], which can be attributed to the up-regulation of amino acid transporters in malignant tissues due- to an often increased proliferation [87]. In particular, because of the relationship between the expression of aromatic L-amino acid decarboxylase (AADC) and the metabolism of [18F] FDOPA [88, 89], [18F]FDOPA has shown diagnostic advantages in the imaging of neuroendocrine cell-related malignancies like neuroendocrine tumors (NETs) [89–94], pheochromocytoma [95–97], pancreatic adenocarcinoma [98, 99] and neuroblastoma (NB) [100–102] regarding diagnostic efficiency and sensitivity.-


**Table 3.** Summary for clinical application of [18F]FDG [83].

#### **4.11. [18F]FET injection (EP)**

Na+ -independent system L amino acid transporters (LATs) preferentially transports amino acids with large neutral side chains, including L-leucine, L-phenylalanine, and L-tyrosine. O-(2-[18F] fluoroethyl)-L-tyrosine ([18F]FET) (**Figure 2**) [103] belongs to the class of large neutral amino acids, which are transported via specific amino acid transporters especially of LATs [104]. Although data today still not reveal which the transporter(s) responsible for [18F]FET accumulation in cells [105], [18F]FET has been well known for its high uptake in brain tumors and its potential for grading tumors particularly gliomas [106, 107]. Summarily, [18F]FET has been well-investigated in differential diagnosis, grading, prognostication, treatment response assessment, and differentiating pseudoprogression from non-specific post-therapeutic changes [108–110]. Switzerland was- the first country to approve [<sup>18</sup>F]FET PET for clinical use in brain tumor imaging since 2014 [105].

#### **4.12. [18F]FLT ([18F]Alovudine) injection (EP)-**

Cellular proliferation plays an important role in cancer and has been an important imaging target of PET radiopharmaceuticals, especially with the aim targeting of DNA synthesis. Since the approach to the measurement of DNA synthesis in humans was explored in the early 1970s,- based on an antiviral agent developed by Medivir, [18F]fluorothymidine ([18F]FLT, also known as [18F]Alovudine) (**Figure 2**) [111, 112] has been designed with intracellularly trapping of its phosphorylated metabolite within cells [113]. Up to now, [18F]FLT has been widely investigated in oncologic setting comprising tumor detection, staging, restaging, and response assessment- to treatment [114–116] and [18F]FLT imaging has several clinical advantages including noninvasive procedure, three-dimensional tumor images and simultaneous detection of multiple tumor sites [117]. Also, [18F]FLT is capable to evaluate tumor heterogeneity in day-to-day practice [118].

#### **4.13. [18F]FMISO injection (EP)**

Hypoxia means insufficient oxygen availability of a cell occurring both in health and is acknowledged by the observation of Gray *et al.* in the mid-1950s [119, 120]. Hypoxia is an important prognostic indicator of response to either chemotherapy or radiation therapy in cancer management [121, 122]. Hypoxia is also an independent factor for predicting the metastases tendency of a tumor cell, because of its enhancement in DNA mutations of atypical cells and further appearance of more aggressive cells. Consequently, 1-(2-hydroxy-3-[18F]fluoropropyl)-2-nitroimidazole- ([18F]FMISO) (**Figure 2**) [123, 124] is the most established agent for assessing hypoxia and has been used for cancer imaging over the past 30 y for glioblastoma multiforme, non-small-cell- lung cancer, and head and neck tumors [125]. In addition, high accuracy of [18F]FMISO PET imaging for determining the duration of survival without relapses and for predicting the radiotherapy efficiency in patients with malignant tumors of various localizations has been reported- [126, 127]. Furthermore, prognostic potential of [18F]FMISO for the pretherapeutic tumor oxygenation status has been confirmed for glioblastoma multiforme, head and neck cancer, lung- cancer, breast cancer, pancreatic cancer, gynecologic cancers, cervical cancer and sarcoma [127].

#### **4.14. [18F]NaF injection (USP and EP)**

The bone is the most common place of tumor metastases next to the lung and liver [128]. Therefore, early and accurate diagnosis of the metastatic bone diseases thus plays an important role for an establishment of adequate therapeutic strategy [129]. [18F]Sodium fluoride ([18F]NaF) was introduced in 1962 and approved by FDA in 1972 [130]. [18F]NaF is a high sensitive boneseeking PET radiopharmaceutical and is considered as an excellent substitute for traditionally used 99mTc-labeled tracers, because its favorable characteristics of negligible protein binding, and rapid blood pool clearance. With 99mTc supply around the world is gradually become a crisis due to the shortage of 99Mo-source material [131, 132], the clinical use of [18F]NaF keeps increasing worldwide. Additionally, uptake of [18F]NaF reflects blood flow and bone remodeling [133], and [ 18F]NaF have been proposed for the use in detection of benign and malignant osseous abnormalities that also allows the regional characterization of lesions in metabolic bone diseases [134, 135].

#### **4.15. [68Ga]Ga-citrate injection(EP)**

In addition to war and famine, bacterial infection has still been one of major worldwide causes for human morbidity and mortality for centuries [136, 137]. Because of the trapping of gallium in the extravascular compartment for inflammatory or infectious sites with the increased capillary permeability [138], and the iron-like binding characteristics in bacterial siderophores and activated lactoferrin in neutrophils [139, 140], gallium is thought to be indirectly uptaken by macrophages [141, 142] or directly uptaken by bacteria [143]. Thus, [67Ga]gallium citrate ([68Ga]Ga-Citrate) has been used for clinical imaging of infection and inflammation since 1984 [144]. The utilities of [68Ga]Ga-Citrate include the monitoring of osteomyelitis, diskitis, intraabdominal infection, tuberculosis and interstitial nephritis, as well as the localization of infection in patients with cellulitis and abscesses [145, 146].

#### **4.16. [68Ga]Ga-DOTA-TOC injection (EP)**

NETs arised from neuroendocrine cells and are one of slow-growing tumors with year-byyear increased incidence rate and 75% of overall 5-y survival, which is strongly dependent on stage and grade of the tumor [147]. Because NETs has been known for its unique overexpression of somatostatin receptors (SSTrs) on the tumor cells [148], SSTr-targeting PET radiopharmaceuticals provide a promising and useful approach for both diagnostic imaging and further peptide receptor radionuclide therapy (PRRT), such as 68Ga-labeled DOTA-(Tyr3 ) octreotide acetate ([68Ga]Ga-DOTA-TOC) (**Figure 2**) [149]. Because octreotide is a subset of the amino acid in somatostatin and has been demonstrated to avidly bind to SSTr [150], [68Ga] Ga-DOTA-TOC has been recognized for its affinity toward both the type 2 somatostatin receptor (SSTr2) and the type 5 somatostatin receptor (SSTr5) [151–154]. Also, [68Ga]Ga-DOTA-TOC was the first PET radiopharmaceutical to clinically localize to NETs in 2001 [155] and has been widely used in Europe and several other countries to assist the therapy planning and accurate diagnosis of NETs patients [156]. In addition, [68Ga]Ga-DOTA-TOC is valuable for neuroectodermal tumors, Hurthle cell thyroid carcinoma, prostate cancer patients with bone metastases and autoimmune thyroid disease like Graves' disease and Hashimoto's disease [145, 146].

#### **4.17. [82Rb]rubidium chloride (USP)**

Just like previous described [13N]NH3 and [15O]H2 O, [82Rb]Rubidium chloride ([82Rb]RbCl) has been reported for directly proportional relationship between its uptake and MBF since 1954 [157]. In addition, several studies have demonstrated the good diagnostic accuracy of [82Rb]RbCl in monitoring of cardiac flow [158, 159]. Subsequently, 82Sr/82Rb generator (CardioGen-82®) of Bracco Diagnostics has been approved by FDA for clinical cardiac imaging since 1989 (NDA 19–414). Therefore, production and administration of [82Rb]RbCl can be well coordinated with the 82Sr/82Rb generator in clinic [160], although a short half-life (78 sec) of 82Rb. In brief, the clinical advantages of [82Rb]RbCl cardiac imaging include its capacity to accurately quantify MBF and a low delivered radiation exposure for a rest/stress test resulted from its very short half-life [160].

#### **5. Conclusion**

With the development of imaging technology, more and more pharmaceutical industry and hospitals worldwide have paid attentions on clinical potential of PET radiopharmaceuticals. However, because of special characteristics of PET radiopharmaceuticals, current pharmaceutical regulatory is probably inapplicable and would be a hurdle for clinical use of PET radiopharmaceuticals in most countries. Thus, as these official monographs of PET radiopharmaceuticals listing in USP or EP, it is definitely worthy to work together for more pharmacopeia monographs and a PET radiopharmaceutical-specific regulatory for benefits of patient-centered care in the future.

#### **Acknowledgements**

This work has been supported in part by grants from the National Taiwan University Hospital, Grants NTUH107-S3882.-

#### **Conflict of interest-**

We declare no conflict of interest.-

#### **Author details**

Ya-Yao Huang

Address all correspondence to: careyyh@ntuh.gov.tw-

PET Center, Department of Nuclear Medicine, National Taiwan University Hospital, Taipei, Taiwan

## **References**

[1] Schwarz S, Norenberg J, Berridge M, et al. The future of USP monographs for PET drugs. Journal of Nuclear Medicine. 2013;**54**(3):472-475-


VIII. Clinical feasibility of positron cardiac imaging without a cyclotron using generatorproduced rubidium-82. Journal of the American College of Cardiology. 1986;**7**(4):775-789-


## **Applied Radiation Protection Physics**

Khaled Soliman, Ahmed Alenezi, Abdullah Alrushoud, Salman Altimyat, Hasna Albander and Turki Alruwaili

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.79286

#### Abstract

Nuclear medicine is an area where both patients and occupational radiation doses are among the highest in diagnostic imaging modalities today. Therefore, a good understanding and proper application of radiation protection principles are of great importance. Such understanding will allow optimization of practice that will be translated into cost savings for health care administrations worldwide. This chapter will tackle: radiation protection in the routine practice of both diagnostic and therapy applications in nuclear medicine including PET, diagnostic facility design, safety aspects of the common radionuclides used in clinics, the safety of the pregnant and breast feeding patients, radiation effect of exposure to ionizing radiation, and risk estimates. The chapter will discuss the operational radiation safety program requirements applied to Conventional Nuclear Medicine using Gamma Cameras, SPECT/CT, PET/CT, and Radioiodine therapy facilities. The chapter will serve as a quick reference and as a guide to access more detailed information resources available in the scientific literature.

Keywords: radiation protection, safety program, dose limits, physics, PET, SPECT, radionuclide therapy

#### 1. Introduction

Good radiation safety practice in nuclear medicine comprises various components: facility design and construction, local radiation safety rules and procedures, staff training, emergency preparedness, equipment quality assurance, and area and contamination monitoring.

Institutions must develop, document, and implement a radiation protection program covering the scope of practice covered under the license. The use of safety procedures, engineered

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

controls like automatic injectors, movable, and syringe shields are encouraged and must be applied to ensure the radiation protection of staff and the public. The radiation protection program contents and methods of its implementation must be reviewed on an annual basis or up to 3 years [1].

#### 2. Important physics relations and definitions

There are few physics relations that are needed in the planning phase the facility that we like to summarize under this section of the chapter. First, let us define radiation dose:

absorbed dose (D) denotes the quantity of radiation energy absorbed by matter from ionizing radiation, and is defined by:

$$\mathbf{D} = \Delta \mathbf{E}/\mathbf{m} \tag{1}$$

ΔE is the energy imparted by the ionizing radiation in a volume, and m is the mass in that volume.

The dose D is measured in [Gy].

$$1\,\mathrm{Gy} = 1\,\mathrm{[Joule/kg]}\\1\,\mathrm{Gy} = 100\,\mathrm{rad},\\1\,\mathrm{mGy} = 0.1\,\mathrm{rad},\\1\,\mathrm{mrad} = 10\,\mathrm{μGy}\tag{2}$$

Radiation exposure measured in Roentgen (R) with 1 R = 0.87 rad (in water or tissue).

How to use the distance effect to estimate dose rates at certain distances from radioactive sources? We remember that radioactive sources in nuclear medicine could be Tc-99m, Rb-82, and F-18 generators, sealed sources used for calibration, I-131 capsules, and the injected patients.

$$\left|\dot{\mathbf{D}}\_1.\mathbf{d}\_1\right|^2 = \dot{\mathbf{D}}\_2.\mathbf{d}\_2\tag{3}$$

D\_ is the dose rate measured in (μGy.hr�<sup>1</sup> ) and d is the distance that is usually in (m).

The second is the radioactive decay equation given by

$$\mathbf{A} = \mathbf{A}\_0. \mathbf{Exp}\ \ (-\lambda. \mathbf{t})\tag{4}$$

where A is the the activity of the source most often in (MBq). (1 mCi = 37 MBq), λ = ln2/T1/2, T1/2 is the half live of the isotope in units of (time) (sec, min, hrs, or years).

And the third is the relationship between dose and the dose rate

$$\mathbf{D} = \dot{\mathbf{D}}.\tag{5}$$

where D\_ is the dose rate in (μGy.hr�<sup>1</sup> ) and t is the time in (hr). And the next important relation that is often used is the shielding:

$$\mathbf{I} = \mathbf{I}\_{\mathrm{o}} \,\mathrm{B}\,\left(\mathrm{\mu x}\right).\mathrm{Exp}\,\left(-\mathrm{\mu x}\right)\tag{6}$$

where Io is the incident intensity, B (μx) is the build-up function, μ is the linear attenuation coefficient of the shield in (cm�<sup>1</sup> ) that depends on the material used and the radiation energy, and x is the thickness of the shield in (cm).

Radionuclide Half-life Emitted Energy (abundance)\* Gamma dose rate constant in Half value layer in radiation (μGy/hr.m<sup>2</sup> /GBq)\*\*\* lead (mm)\*\* 11C 20.5 min β<sup>+</sup> (ɣ) 0.39 MeV (100%) 139.3 4.95 18F 109.8 min β<sup>+</sup> (ɣ) 0.24 MeV (96.9%) 135.1 4.96 32P 14.2 days β� 0.695 MeV (100%) Pure beta emitter Pure beta emitter 51Cr 27.7 days ɣ 0.32 MeV (9%) 4.22 1.92 57Co 271.7 days ɣ 0.122 MeV (86%) 14.11 0.298 68Ga 68 min β<sup>+</sup> (ɣ) 0.74 MeV (88%) 129 5.12 89Sr 50.5 days β� 0.585 MeV (100%) Pure beta emitter Pure beta emitter 89Zr 78.4 hrs β<sup>+</sup> (ɣ) 0.897 max MeV 22.3%) 123.4\* 9.02 ɣ 0.909 (99%) 90Y 64 hrs β� 0.93 MeV (100%) Pure beta emitter Pure beta emitter 99mTc 361.2 min ɣ 0.140 MeV (89%) 14.1 0.234 111In 67.4 hrs ɣ 0.172 MeV (89%) 83.13 0.257 0.247 MeV (94%) 131I 8.04 days β�, ɣ 0.19 MeV 90%) 52.2 2.74 β� 364 keV (83%)ɣ<sup>1</sup> 0.637 MeV (7%) ɣ<sup>2</sup> 133Xe 5.25 days β�, ɣ 0.10 (100%) β� 14.33 0.0379 0.081 (37%) ɣ 153Sm 1.95 days β�, ɣ 0.23 MeV (50%) β� 12.2\* 0.0876 0.103 MeV (28%) ɣ 177Lu 6.73 days β�, ɣ 0.15 MeV (79%) β� <sup>1</sup> 4.7\* 0.542 0.12 MeV (9%) β� 2 198Au 2.7 days β�, ɣ 0.32 (99%) β� 54.54 3.35 0.40 (96%) ɣ 201Tl 73 hrs ɣ, x 0.167 MeV (8%) ɣ 10.22 0.258 0.070 MeV (74%) x1 0.080 MeV (20%) x2 \*

Exp (�μx) is the attenuation factor [2].

Calculated from Ref. [3].

\*\*Taken from Ref. [3].

\*\*\*From Ref. [4].

Table 1. Radionuclides of interest in diagnostic and therapeutic nuclear medicine. The energy is the average β emission in MeV.

Other important definitions are one relating the shielding material halve (HVL) and tenth value layers (TVL) with μ measured in (cm�<sup>1</sup> ).

$$\text{HVL} = \ln \, 2/\mu \,\text{and } \text{TVL} = \ln \, 10/\mu \tag{7}$$

Another important relationship is the one relating a radioactive source specific Gamma Ray Constant known \_ as г and the dose rate D

$$\dot{\mathbf{D}}\ (\mathbf{t}) = \mathbf{r}.\mathbf{A}\ (\mathbf{t})/\mathbf{d}^2\tag{8}$$

<sup>2</sup> Г is in (μGy.hr�<sup>1</sup> . m . mBq�<sup>1</sup> ), the activity A at time (t) in (MBq), and the distance d in (m).

And the total dose is the integration of the dose rate over the total time.

$$\mathbf{D} = \int \dot{\mathbf{D}} \, \mathbf{d} \mathbf{t} \tag{9}$$

The above-mentioned relations are the fundamental ones know as time, distance, and shielding that need to be used in radiation protection applied to nuclear medicine (Table 1). There are other useful relations such as:

$$1\,\text{Sv} = 100\,\text{rem},\\1\,\text{rem} = 0.01\,\text{Sv},\\1\,\text{mrem} = 10\,\mu\text{Sv}.\tag{10}$$

#### 3. Nuclear medicine facility design and shielding evaluation

#### 3.1. Typical nuclear medicine department

A typical nuclear medicine facility contains the following rooms or areas: (1) reception area; (2) waiting room; (3) hot lab; (4) imaging room(s); (5) thyroid uptake room; (6) physician office(s); (7) chief technologist office; (8) hallways; and (9) bathroom(s). For regulatory purposes, these areas are considered to be either restricted or unrestricted areas [5].

The following devices are used in typical nuclear medicine hot lab: (1) dose calibrator; (2) fume hood; (3) shielding material (such as lead and leaded glass for use in the hot lab, pigs, syringe holders, syringe shields, aprons, and portable shields); (4) protective clothing (laboratory coats and gloves); (5) radioactive waste storage containers; (6) sealed calibration sources (for dose calibrator, well counter, and gamma camera); (7) survey meters and exposure meters; (8) well counter; (9) whole-body/ring dosimeters; and (10) individual room exhaust systems and activated charcoal gas traps [5].

#### 3.2. Facility general requirements

All rooms, where radioactive materials are used and stored, shall have the appropriate radiation signs posted at the entrance door; gamma camera rooms, dispensing rooms, and hot laboratories are controlled areas, and therefore, access to unauthorized personnel shall be restricted. The hot lab shall be provided with a fume hood with proper exhaust and filters for handling volatile radionuclides. All radionuclides shall be stored in shielded containers.

All containers of radioactive materials shall be labeled with a radiation sign and with the word "Caution: Radioactive Material" with the name of the radionuclide, its chemical form, activity, and expiry date/time if applicable.

The radioactive waste bags/container shall have a label with date of disposal [1].

#### 3.3. Radiation shielding design

Structural shielding should be considered in a busy nuclear medicine facility where large activities are handled and where many patients are waiting and examined. In a PET/CT facility, structural shielding is always necessary and the final design will generally be determined by the PET application because of the high activities used and because of the high energy of the annihilation radiation.

Careful calculations should be performed to ensure the need and construction of the barrier. Such calculations should include not only walls but also the floor and ceiling and must be made by a qualified medical health physicist. Radiation surveys should always be performed to ensure the correctness of the calculations [5].

The shielding design goals in accordance with NCRP 147 standard are as follows.

It is always recommended to pay extra attention when performing initial facility design by assigning the task to a qualified medical health physicist with board certification to perform the shielding calculations and or to review and approve the shielding design. Such action, at the planning stage, is meant to avoid future problems and to save unnecessary cost resulting from redesigning the facility or installing additional structural shielding materials.

The medical physicist should do the following:


So far, we have calculated the weekly dose expected to be present in an area that requires protection using:

$$\mathbf{D\_w \left[ \mathbf{mGy/week} \right]} = \dot{\mathbf{D\_0}} \left[ \mathbf{mGy/hr} \right]^\* \left( \mathbf{d\_l[m]/d\_2[m]} \right)^{2\*} \text{ET \left[ hr/week \right]} \tag{11}$$

The calculated Dw in (mGy/week) is compared with DL in (mGy/week) from Table 2 (shielding design goal). The calculated dose rate in the area that needs to be protected is evaluated against the weekly effective dose limits from Table 2. The structural shielding is found


Table 2. Structural shielding design goals.

acceptable if the dose per week is below 0.2 or 0.01 mSv per week for controlled and uncontrolled areas, respectively. For more details, it is recommended to have a copy of NCRP report 147 for frequent consultations and references.

The DL use must be multiplied by the occupancy factor (OF) in the area that needs to be protected. The following is a list of OF from the NCRP 147 report (Table 3).

The linear attenuation coefficient (μ) describes the fraction of a beam of X- or gamma-rays that is absorbed or scattered per unit thickness of the absorber in (cm).

The attenuation factor is calculated as: (AF) = Exp (�μx) = DL/Dw, assuming the buildup factor B (μx) = 1, which is valid using the point source approximation. The buildup factor is the factor by which the total value of the quantity being assessed at the point of interest exceeds the value associated with only primary radiation. The total value includes secondary radiations especially scattered radiation.

Then, we have

$$\text{Ln}\ (\text{D}\_{\text{L}}/\text{D}\_{\text{w}}) = -\mu\text{x} \text{ or } \text{Ln}\ (\text{D}\_{\text{w}}/\text{D}\_{\text{L}}) = \mu\text{x} \tag{12}$$

Knowing μ depending on (material & energy) from tables [6, 7], we can calculate the required thickness of the shielding material x given by:

$$\times \text{[cm]} = \text{Ln } (\text{D}\_{\text{w}}/\text{D}\_{\text{L}}) / \mu \text{ [cm}^{-1}] \tag{13}$$

#### 3.4. Shielding survey

An area survey report is always required by the regulatory authorities after structural shielding installation and before routine operations of the facility. The report includes dose rate measurements in various locations behind the installed barriers and an evaluation of the weekly effective


Table 3. List occupancy factors.

dose for the controlled and uncontrolled areas when appropriate. The reported results shall confirm the adequacy of the shielding installed.

#### 4. Local rules and regulations

The facility's management must sign the license application and has authority for the radiation protection program. The radiation safety officer is appointed by management and must accept, in writing, responsibility for implementing the radiation protection program. The nuclear medicine physicians are also part of the license and described as authorized users. The licensee must periodically (at least annually) review the radiation protection program content and the efficiency of its implementation [1].

Licensees must provide individual dose monitoring devices: TLD or OSL badges to each of the following staff:


## 5. Quality control (QC) program

When imaging equipment is first installed, a qualified medical physicist performs a set of tests in order to document the equipment performance and to ensure that it meets the agreed technical specifications between the vendor and the hospital. The National Electrical Manufacturers Association (NEMA) in the United States has defined tests that allow equipment performance testing and comparison between different machines and vendors. Quantitative data acquired during the specified tests are gathered and kept for evaluating the equipment performance overtime to detect any deterioration. This helps detecting problems early, since gradual deterioration of performance is detected on the curve even before the performance deteriorates beyond the specifications. Quality control program needs continuous monitoring: if you do not insist on quality control measurements, the QC program will silently die, and image quality will slowly deteriorate [8, 9].

A quality standard requires that QC program for all equipment used in imaging the patients to be performed on a regular basis and documented. There is a major trend worldwide for hospitals to implement a quality management programs (QMP) for all imaging services provided; such QMP includes a radiation safety program (RPP) aimed to protect patients and staff working in the diagnostic imaging departments.

The QC program must include well counters, dose calibrators, gamma counters, automated dispensing/injection system, and radiation survey meters.

Also, the IAEA basic safety standard (BSS) requires a quality assurance program (QAP) to be part of the facility QMP. Therefore, it is recommend to integrate both RPP and QAP into the facility wider QMP to fulfill the requirements of the Joint Commission International (JCI) for example.

## 6. Occupational dose limits

Radiation exposure to staff working in nuclear medicine occurs from radiopharmaceutical dose preparation, injection of the activity to the patients, and escorting and supervising the patient during image acquisition. The application of the three principles in radiation protection allows staff to considerably decrease the level of radiation exposures. Time, distance, and shielding must be applied for good radiation protection practices.

The good news is the administered activities, which are generally low and most of the used radiopharmaceuticals have short half-lives, and the resulting level of radiation exposure, organ doses, and effective doses are low and do not pose high risk to individuals working in nuclear medicine services and also for the patients. However, regulations require that all occupational exposures both external and internal must be assessed and reduced as much as possible the ALARA principle. Therefore, licensees must comply with the following dose limits for occupationally exposed staff (Table 4).


Table 4. Recommended dose limits as per latest ICRP recommendations (ICRP 103, 2007) [10].

#### 7. Radioactive contamination control and spill procedure

The following is a typical spill procedure that can be implemented as part of the radiation protection program:


and place in a plastic bag. If an individual is contaminated, rinse contaminated area with water and wash with a mild soap, using gloves.


## 8. Ordering receiving and opening radioactive packages

Good practice recommends performing wipe test on every radioactive packaged received, and it is the responsibility of the RSO to perform the test and document the results.

Ordering radioactive material is through licensed/authorized service providers and authorized to transport radioactive materials under national radiation protection regulations. When ordering radioactive materials for extended period of time is also recommended to check the maximum total activity licensed and not to order more than the maximum in order to avoid any license violations or noncompliance. The RSO must authorize each order of radioactive material and must maintain proper database and records as specified in the nuclear medicine license.

Generally, transportation of radioactive sources in any country follows the international atomic energy agency (IAEA) regulations for the safe transport of radioactive materials. The IAEA regulations include details about the shape and the labeling of packages to ensure mechanical and physical safety during the transport including the potential exposure to water and flames [14, 15].

There are three different labels: I–White, II–Yellow, and III–Yellow. In all cases, the radionuclide and its activity should be specified. The label gives some indication of the dose rate D at the surface of the package:

Category I–White D ≤ 0.005 mSv/h Category II–Yellow 0.005 < D ≤ 0.5 mSv/h Category III–Yellow 0.5 < D ≤ 2 mSv/h

#### 9. Radiation surveys and instrument calibration requirements

#### 9.1. Routine area surveys

Regular radiation area monitoring is required by regulations. Records must be kept in file for compliance purposes. Some areas need more attention in Nuclear Medicine Departments such as the radiopharmacy, where the large amount of radioactive materials is manipulated. Therefore, permanent area monitors can be installed and sometimes are required by the national regulators. Area monitors could be scintillation counters or ionization chamber type with audible signal for dose rate monitoring. The radiation area monitoring program is sensitive to potential increase of activity in the radiopharmacy and new added radionuclides to the list of radionuclides used at the department. It also serves as a warning to staff in the case of unshielded radiation source that is exposed in the work area [16].

#### 9.2. Radiation measuring instrument calibration requirements

Regulatory authorities require licensees to have an instrument capable of measuring radiation dose rates in the order of (1–1000 μSv/hr) ready to be used at all times in nuclear medicine departments [1]. Periodic calibration of instrument is a regulatory requirement in most countries. Such calibration must be performed by an authorized center licensed to calibrate radiation detection and measurement instruments for dosimetry and radiation protection purposes.

Records of calibration certificates must be maintained with the RSO, and proper sticker are recommended to be on the surface of the calibrated instrument indicating the validity date of the calibration and the due date of next calibration.

## 10. Caution signs and posting requirements

Area postings are required by regulations. In most countries, posting requirements are specified as part of the license document called license conditions or as part of the written document that contains the current radiation protection regulations. Copies of such documents must be available at the radiation protection office for consultations when needed.

#### 11. Labeling containers, vials, and syringes

Syringe and vials that contains radioactive materials must be labeled with the isotope, activity, time, date, and technician or radiopharmacist signature at all times when stored or in transit to be administered to the patients for both injections and oral administration routes.

## 12. Determining patient dosages and radiation effects

Because of the low administered activities and short half-lives of radiopharmaceuticals used in diagnostic nuclear medicine practice, the resulting radiation doses (both organ doses in rad and effective dose equivalents in rem) pose extremely low radiation risks.

Concerns about stochastic radiogenic risks have led to NRC regulations for diagnostic nuclear medicine that inherently demand a radiation protection philosophy based on the conservative hypothesis that some risk is associated with even the smallest doses of radiation.

There is no question that exposure of any individual to potential risk, however low, should be minimized if it can be readily avoided or is not accompanied by some benefit. The weighing of risks and benefits, however, is not always based on objective data and calls for personal value judgments, which can vary widely.

Today, after more than a century of careful review of the evidence for radiation effects from the radiation doses associated with diagnostic nuclear medicine, there appears to be little reason for apprehension about either genetic or somatic effects (including thyroid cancer).

#### 13. Risk assessment of the pregnant and breast feeding patient

#### 13.1. Pregnant patients

Pregnancy is not an absolute contraindication to radionuclide studies. If a patient is pregnant, it is imperative to discuss the indications for the study with a departmental medical officer, and the fact that the patient is pregnant must be clearly marked on the consultation form. A smaller than normal activity of radiopharmaceutical may be administered, thereby minimizing radiation to the fetus. There is little risk involved with the use of 99mTc radiopharmaceuticals, but studies with other radionuclides should be avoided unless clinically justified [16].

If a pregnant patient undergoes a diagnostic nuclear medicine procedure, the embryo/fetus will be exposed to radiation. Typical embryo/fetus radiation doses for more than 80 radiopharmaceuticals have been determined [17].

There should be no concern about radiation exposure below 150 mSv to pregnant patient. Most of the calculated doses to the embryo fetus are below 18 mSv except for 67Ga which is 18 mSv. Radiation doses received from a diagnostic medical imaging procedure are not high enough to cause a spontaneous abortion.

Radioiodine 131I is widely used for therapy of hyperthyroidism and thyroid cancer. Its use is generally contraindicated in pregnancy, as large doses to the fetus and fetal thyroid may result due to the passage of the radioactivity across the placenta.

Ref.[18] has a table showing the injected activityand the corresponding calculated dose to the fetus. Also, ICRP has published two other documents [19, 20] having more information about radiation doses received by the fetus as results of the injection of radiopharmaceuticals to the mother.

#### 13.2. Breast feeding patients

In situations involving the administration of radiopharmaceuticals to women who are lactating, the breastfeeding infant or child will be exposed to radiation through the intake of radioactivity in the milk, as well as external exposure from close proximity to the mother. Radiation doses from the activity ingested by the infant have been estimated for the most common radiopharmaceuticals used in diagnostic nuclear medicine [21].

Many radionuclides may be concentrated in breast milk. This may mean that the patient has to stop breastfeeding for a period of time. Table 8.1 (p. 516) in Ref. [16] gives a guide to the period of time that breast feeding must be interrupted.

In most cases, no interruption in breast feeding was needed to maintain a radiation dose to the infant well below 100 mrem (1 mSv). Only brief interruption (hours to days) of breast feeding was advised for 99mTc-macroaggregated albumin, 99mTc pertechnetate, 99mTc -red blood cells, 99mTc-white blood cells, 123I-metaiodobenzylguanidine, and 201Tl. Complete cessation was suggested for 67Ga-citrate, 123I sodium iodide, and 131I sodium iodide. The recommendation for 123I was based on a 2.5% contamination with 125I, which is no longer applicable.

## 14. Diagnostic reference levels (DRLs)

Diagnostic reference levels are published by many countries across the globe for both adult and pediatric patients. Such levels are published and made public by national authorities in radiation protection in medicine.

Establishing DRLs is recommended even at the local level in order to bench mark the practice against well-established ones. Use of the reference levels is a way of optimizing the clinical practice and fulfills quality standard requirement such as JCI and national regulations. Table 5 contains a list of administered activities for the most common nuclear medicine exams with a range and maximum recommended values when applicable.



Table 5. Radiopharmaceutical administration activity in adults (weight is 70 kg).

## 15. Sealed sources inventory and leak testing

Nuclear medicine is a regulated practice in most countries around the world through a rigorous system of licensing and inspections. Most regulations require a biannual inventory and leak testing of all sealed sources used under the practice license.

Sealed sources by nature pose minimum risk of contamination because they are well designed and optimized to prevent leakage; however, they must be tested on a regular basis.

#### 15.1. Inventory requirement

Inventory list will contain the following information: source locations (e.g., hot lab), model number, radionuclide, nominal activity, and the name of the individual who performed the inventory. Inventory records should be maintained for a minimum of 3 years.

Most of the international radiation protection regulations require licensees to notify the regulatory authority in case of loss of any licensed radioactive source or materials. Effort must be deployed in order to recover the lost source or locate them.

#### 15.2. Leak testing requirement

Sealed sources must be wiped in order to detect any removable contamination, must commonly every 6 months or as per license condition requirements.

Cotton swabs or filter or tissue paper can be used to take the wipe sample, and samples must be well identified before proceeding to the sample counting stage to prevent mixing of results.

The person performing the wipe must wear disposable gloves and protective clothing and change the glove after each source in the case of performing wipe testing of multiple sources at the same time and location in order to avoid cross contamination and repeating the wipe testing which may be time consuming.

Counting the wipe samples can be done by using a routine gamma counter, sodium iodide scintillation counter, or by using a Geiger-Muller detector with pancake prop. In case of Geiger or scintillation counter type, the following equation can be used in order to report the results in the proper units.

$$\text{Activity (MBq)} = \left[ \text{wipe (cpm)} - \text{BG (cpm)} \right] / \epsilon \text{ (cpm/MBq)} \tag{14}$$

where e (cpm/MBq) is the detector efficiency measured in counts per minutes (cpm) per activity in (MBq).

The analysis must be capable of detecting the presence of 185 Bq of radioactive material on the test sample and must be performed by an authorized service provider. An activity of more than 185 Bq on the test sample is considered as leaking source and must be declared to the regulatory authority.

#### 16. Decay in storage and waste management

Radioactive waste from nuclear medicine procedures can be dealt with either by simply storing the waste safely until radioactive decay has reduced the activity to a safe level or possibly by the disposal of low activity waste into the sewage system, if permitted by the local regulatory authority. Long half-life or high activity waste may need long term storage in a suitable storage area.

Technetium-99m waste normally requires storage for only 48 hours, in a plastic bag inside a shielded container. The container should be labeled with the radionuclide and date. Gallium-67, iodine-131, and other longer half-life materials should be placed in a separate labeled and dated plastic bag and stored safely. Sharp items, such as needles, should be separated and placed in a shielded plastic container for safety.

In some countries, the radiation dose rates at the surface of the cleared waste bags and released into normal waste must be measured before disposal. A dose rate limit maybe applied by regulations. Normally, a maximum dose rate of 5μGy/hr. is imposed. Disposable gloves should be worn and caution exercised when handling sharp items. Any labels and radiation symbols should be removed. Radioactive waste should be placed in a locally appropriate waste disposal container, for example, a biological waste bag (since waste, once no radioactive, is usually regarded as biological waste). Placement of waste inside two bags is advisable to minimize the risk of spillage [25].

#### 17. Safety instructions for workers

#### 17.1. General safety procedures


#### 17.2. Radiopharmaceutical therapy safety procedures

Radionuclide therapy presents relatively few hazards to staff and patients, but there are a number of common principles of radiation safety that have to be observed.

Staff caring for or working with patients who have received therapy with radionuclides may be required to follow safe working practices, according to the type of therapy. These are listed in Section 5.2. (IAEA, 2006) [16], we are going to summarize the most important aspects in the mentioned reference here below.

The most common safety procedures include the following: during the pre-therapy stage, testing the female patient for pregnancy is important, and advice to the physician and to the patient can be done by the qualified medical physicist certified in medical health physics or in health physics.

On the admission day for the therapy as inpatient treatment at the hospital, physician guidelines, administrative protocol, advice to nursing staff, and preparation of patient room must be done.

During the therapy days stay at the hospital, control of radioactive waste including urine, contaminated syringes, cotton swabs, and other items must be controlled. Control of visitors, patient, and local environment must be monitored.

At the discharge time, information to the patients must be given and advice on future pregnancies. The patient should be given a discharge card listing the radionuclide and activity administered the activity on discharge and any necessary precautions.

Table 6 includes the discharge criteria that can be applied in the absence of national or local regulations:


Table 6. Radioactive patient discharge limits.

#### 17.3. Emergency department safety procedures

The emergency room (ER) in the medical city should be prepared to assist in an incident with contaminated wounds, and the staff in ER shall be made familiar with radiation decontamination procedures. Such information is available in documents such as references [26, 27]. Let us review the general guidelines to be applied in case of emergencies involving radioactive materials: accidents or incidents such as radioactive spills, skin contamination, traffic accidents, loss of radioactive materials, and use of radiological dispersal devices; in most cases are not life threatening situations. The hazard from radiation exposure to emergency attending staff is little. Therefore, the patient must be treated first and immediately with no consideration of the level of contamination. The patient life must be saved first. Injured patients may be covered with disposable material to prevent any spread of contamination into the hospital facilities. Safe decontamination procedures can be initiated later after the patient has been stabilized.

The basic radiation protection methods of increasing the distance from the radiation source, reducing the time spent close to the source, and use shielding martial between the person and the source can be done when possible. In the current situation, the contaminated patient body is the radiation source.

Personal protective equipment such as gloves, masks, and shoe cover must be used when working on a contaminated injured patient. Counting the amount of contamination on the skin can be done using appropriate radiation detector. Clean the contaminated area by going to the nearest sink, wash with mild soap, and cool to warm water.

Wiping the contaminated area with a filter paper and counting the activity removed on that piece of paper will indicate the amount of activity that can be removed while performing the physical decontamination while a close survey of the contaminated area will give an indication of the total contamination both fixed and removable.

In the case of suspected internal contamination through open skin wounds, inhalation or ingestion of radioactive substances, it may be necessary to take urine samples or performing thyroid uptake counting, the evaluation of internal contamination must be dose by an experienced health physicist (Table 7).


Table 7. A list of types of radiation detectors and their potential use.

## 18. Radioiodine therapy and patient release criteria

Radioiodine therapy is one of the most common methods used in radionuclides therapies worldwide; therefore we have included this section to summarize the most important radiation safety aspects related to this treatment for both the patient and the hospital staff caring for the patients. In the literature, there are a lot of references covering all aspects of radioiodine therapy.

This section will consider a summary of applicable requirements for patient accommodation (design requirements including shielding), as well as radiation safety procedures necessary for safe practice.

#### 18.1. General safety principles

Doors of rooms that are occupied by patients undergoing radioiodine therapy shall be posted with the appropriate radiation sign. These rooms are also considered as controlled areas during the stay of the patients, and therefore access shall be restricted to members of the public. A specially designed room/ward is required for radionuclide therapy if therapeutic dose of I-131 is to be administered; bed shields shall be available in the rooms of patients undergoing radioiodine therapy.

A nonporous, easily decontaminated floor and wall surfaces with covered junctions to make cleaning easier;

A dedicated shower and toilet, the toilet draining directly to the main sewer or to a system of radiation waste disposal, depending on local regulatory requirements.

A physical barrier to entry: a simple door may be sufficient; moveable lead shields to minimize nursing exposure.

The possible installation of a remote patient monitoring system (video); door signs prohibiting entry by pregnant women, children, and other persons without permission, giving a time limit for approved visitors.

It is not allowed to remove anything from the room without clearance and requiring the use of protective clothing in the room. Rubbish must be kept within the suite until dealt with by a physicist. A designated place to keep supplies of disposable gloves and gowns, and possibly overshoes, outside the room shall be made available; storage within the room for collection and temporary storage of waste.

The patients are advised to have adequate hydration and voiding frequently and flushing the toilet twice after each voiding. Patient comfort should be catered for by radio, television and/or videotape facilities as well as a comfortable (but easily decontaminated) chair. Disposable sheets, blankets, and eating utensils should be provided. When the patient is ready for discharge, all the patient's belongings must be checked for radioactive contamination and stored or washed separately as necessary.

No member of staff should enter the therapy room without wearing a personal radiation monitor. Persons entering the room should put on plastic aprons, gloves, and shoes. As the barrier is crossed on leaving the room, this protective clothing must be removed and placed in the disposal bag provided [5].

#### 18.2. Patient release criteria

After hospitalization, the patient undergoing radioiodine therapy treatment is released from the hospital to normal life at home and work. Regulators across the world developed release criteria for the patient to fulfill before his release from the confinement in the hospital. The aim of the regulation is to protect the patient family members and the general public from unnecessary exposure to radiation while living in the same area with the released radioiodine therapy patient.

There is no solid agreement on the patient release criteria among countries in the world today; Table 8 summarizes the current release criteria applied in the majority of countries.

Release criteria 1 in the table is based on the administered activity; if the patient receive less than 110 MBq, he or she are automatically released from hospital like any other diagnostic nuclear medicine exam using other radiopharmaceutical than I-131. Criteria number 2 is based on the remaining activity in the patient's body upon release; such activity is estimated based on measurements by the hospital radiation protection staff or the RSO. Criteria number 3 is based on the direct dose rate measurement at 1 meter from the patient using a calibrated instrument. The last criteria number 4 is used in the United States where licensee may release a patient if dose calculations using patient-specific parameters, which are less conservative than the conservative assumptions, show that the potential total effective dose equivalent to any individual would be not greater than 5 mSv [28].


Table 8. Summary of radioiodine patient release criteria in the world.

#### 19. Incidents and misadministration

A variety of incidents may occur in nuclear medicine practice which can result in the inadvertent radiation exposure of a patient, a member of the public or a staff member. These include according to reference [29]:


What primary actions should be taken in case of a misadministration?


#### 20. Conclusion

In this chapter, we have attempted to include the necessary information needed by radiation safety officer or medical physicist responsible for the radiation protection of the nuclear medicine department. The chapter may also serve as a guide for clinicians with an overall responsibility of the radiation safety program and the licensing of the facility. The chapter includes links to more comprehensive references in radiation protection applied to nuclear medicine.

#### Author details

Khaled Soliman<sup>1</sup> \*, Ahmed Alenezi<sup>2</sup> , Abdullah Alrushoud1 , Salman Altimyat1 , Hasna Albander<sup>1</sup> and Turki Alruwaili1

\*Address all correspondence to: khaledsolimna61@gmail.com


#### References


#### **Chapter 6**
