28-5-19 3rd

Evaluation of Implementation of Standard Requirements on
Clinical Use of New Radiopharmaceutical
Iqra Anwar
2019
Department of Physics & Applied Mathematics

Pakistan Institute of Engineering and Applied Sciences
(PIEAS)
Nilore, Islamabad 45650, Pakistan
i
“Knock, And He'll open the door
Vanish, And He'll make you shine like the sun
Fall, And He'll raise you to the heavens
Become nothing, And He'll turn you into everything.”
― Jalal ud-Din Rumi
ii
Evaluation of Implementation of Standard
Requirements on Clinical Use of New
Radiopharmaceuticals
Iqra Anwar
2019
Department of Physics & Applied Mathematics

Pakistan Institute of Engineering and Applied Sciences
(PIEAS)
Nilore, Islamabad 45650, Pakistan
iii
Evaluation of Implementation of Standard Requirements on
Clinical Use of New Radiopharmaceuticals
IQRA ANWAR
A Thesis Submitted to the Faculty of Applied Sciences of Pakistan Institute of

Engineering and Applied Sciences (PIEAS) in partial fulfillment of the Requirement
for the degree of M.S. Medical Physics
iv
v
Declaration of Originality
I hereby declare that the work contained in this thesis and the intellectual content of
this thesis are the product of my own work. This thesis has not been previously
published in any form nor does it contain any verbatim of the published resources
which could be treated as infringement of the international copyright law.
I also declare that I do understand the terms ‘copyright’ and ‘plagiarism’ and that in
case of any copyright violation or plagiarism found in this work, I will be held fully
responsible of the consequences of any such violation.
Signature __________________
(Iqra Anwar)
24 May, 2019
PIEAS, Islamabad.
vi
Certificate for Approval
This is to certify that the work contained in this thesis entitled: “Evaluation of
Implementation of Standard Requirements on Clinical Use of New
Radiopharmaceutical” was carried out by Miss Iqra Anwar, and in my opinion is
fully adequate, in scope and quality, for the degree of MS. Medical Physics.
Supervisor:____________
Dr. Muhammad Shahid (PSO),
24 May, 2019
NISAS, PNRA, G8/1,Mauve
Area, Islamabad
Co-Supervisor:____________
Mr. Tariq Siddique (PSO)
24 May, 2019
PIEAS, Islamabad
Head of DPAM: ____________

Dr. Muhammad Yousaf
Hamza (DCS)
24 May, 2019
PIEAS, Islamabad
vii
ACKNOWLEDGEMENT
Praise to almighty ALLAH, the most Benign and Compassionate Who bestowed upon
me, the strength and wisdom to complete this research work. To Him be all praises for
equipping His humble creature with keen penetrating mental faculty. Moreover, salute
to the Holy Prophet Muhammad (Sallallaho Alaihe Wasallam), the sole reason behind
the creation of this universe and a torch of guidance and knowledge for humanity.
I am deeply indebted to my respected supervisor Dr. Muhammad Shahid (PSO),
Principle Scientific Officer at PNRA, for assignment of topic, advice guidance,
patience, support and willingness to listen and help during the progress of my research
work.
I am deeply obliged to my Co-supervisor Mr. Tariq Siddique (Principle Scientist)
for his enormous help and valuable guidance during experimental work and thesis
writing. I would also like to express my deep sense of gratitude to the respectable Dr.
Yousaf Hamza”, Deputy Chief Scientist and Head of DPAM, who provided me
necessary facilities during my research work . I also owe debt of gratitude to who
remembered me in their prayers for my success throughout the span of my studies.
Finally, I would like to pay my special thanks from the core of my heart to all those
sacred personalities who keep me close in their thoughts and prayers and indirectly
play part in my prosperity.
Iqra Anwar
MS. Medical Physics
PIEAS,
Nilore, Islamabad
May, 2019
viii
Table of Contents
1 Introduction ................................................................................................................. 1
1 Radiopharmaceuticals ................................................................................................. 1
1.1 Mechanism of action ....................................................................................... 1
1.2 Clinical uses of Radiopharmaceuticals ........................................................... 2
1.3 Dosimetry of Radiopharmaceuticals ............................................................... 3
1.3.1 Internal dosimetry is helpful to ............................................................... 4
1.3.2 Dosimetric systems .................................................................................. 4
1.4 Quality control of Radiopharmaceuticals ....................................................... 5
1.5 Dosimetry of radiopharmaceuticals ................................................................ 8
1.6 Dosimetry Quantities and Units ...................................................................... 9
Absorbed dose ........................................................................................................ 9
Equivalent dose ...................................................................................................... 9
1.7 Medical Internal Radiation Dose System ........................................................ 9
1.8 RAdiation Dose Assessment Resource (RADAR)........................................ 10
1.8.1 Usefulness of the Dosimetry Systems.................................................... 10
Models and Resources for Internal Dose Calculations Standardized ...................... 11
1.9 Input Data for Dose Calculations .................................................................. 11
1.9.1 Extrapolation of Animal Data ................................................................ 12
Image Quantification ........................................................................................... 12
1.9.2 Dose due to Radiocontaminants in Radiopharmaceutical Product .Error!
Bookmark not defined.
1.9.3 Biological endpoints .............................................................................. 14
2 Novel Radiopharmaceuticals ............................................................................... 17
2.1 Radionuclide 11C .......................................................................................... 18
2.2 Radionuclide 15O......................................................................................... 18
2.3 Radionuclide 13N......................................................................................... 19
2.4 Production and Demand of Radioisotopes .................................................... 19
2.5 Locally produced ........................................................................................... 19
2.5.1 Radionuclide 18F .................................................................................. 20
2.6 Imported ........................................................................................................ 20
2.7 Intended to Buy ............................................................................................. 20
2.8 LUTITIUM 177............................................................................................. 20
2.8.1 Production .............................................................................................. 20
2.8.2 Decay Characteristics............................................................................. 21
2.8.3 Clinical Applications of 177Lu .............................................................. 22
2.9 QUALITY CONTROL OF 177Lu PRODUCED BY A REACTOR ........... 23
2.10 Gallium 68 ................................................................................................. 24
2.10.1 Radionuclide 68Ga................................................................................ 24
2.10.2 Production .............................................................................................. 24
2.10.3 Clinical applications............................................................................... 25
2.11 QUALITY CONTROL OF 68Ga .............................................................. 25
2.11.1 Quality Control Of 68Ga Obtained from a 68Ge/68Ga Generator ........ 25
Identity ................................................................................................................. 27
Radionuclidic purity............................................................................................. 27
Chemical purity.................................................................................................... 28
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2.11.2 Regulatory Aspects Of Ge\Ga 68 Generator ......................................... 28
2.11.3 Quality Control Of 68Ga Produced By Cyclotron ................................. 28
2.12 Quality Control Of 213Bi Obtained From A 225Ac/213Bi Generator ..... 30
2.12.1 Biokinetic studies ................................................................................... 30
2.13 Regulatory Aspects of Dose Calculations ................................................. 31
3 LITERATURE REVIEW .................................................................................... 34
4 MATERIALS AND METHODS ......................................................................... 42
4.1 FDG18 ........................................................................................................... 42
4.2 Synthesis of FDG: ......................................................................................... 43
4.2.1 Step 1: Irradiation of 18O water with protons ....................................... 43
4.2.2 Step 2: Extraction of [18F] fluoride the H2O18 .................................... 44
4.2.3 Step 3: Drying of [18F]fluoride ............................................................. 45
4.2.4 Step 4: Labelling of the mannose triflate with the 18F .......................... 45
4.2.5 Step 5: Removal of the protective acetyl groups by hydrolysis to form
FDG 45
4.2.6 Step 6: Purification and formulation of the final FDG product ............. 46
4.2.7 Step 7: Sterilizing filtration .................................................................... 46
4.2.8 Step 8: Sampling for quality control and quality assessment ................ 47
4.2.9 Step 9: Dispensing ................................................................................. 47
4.2.10 Step 10: Packaging and shipping ........................................................... 47
4.3 Quality Control of F18-FDG ......................................................................... 48
4.3.1 Radiochemical Purity and Radiochemical Identity................................ 49
4.3.2 Filter Integrity test.................................................................................. 49
4.3.3 Residual Solvent .................................................................................... 49
4.3.4 Stabiliser Test......................................................................................... 50
4.3.5 PH .......................................................................................................... 50
4.3.6 Sterility testing ....................................................................................... 50
4.3.7 Bacterial Endotoxin test ......................................................................... 51
4.4 FDG18 quality control specifications according to European
PHARMACOPIEA .................................................................................................. 51
5 RESULTS AND DISCUSSIONS ........................................................................ 52
5.1 Evaluation of quality control and dosimetric Facilities at INMOL
HOSPITAL WITH RESPECT TO IAEA STANDARD SPECIFICATIONS ........ 52
5.1.1 FDG 18................................................................................................... 53
5.1.2 GALLIUM 68 ........................................................................................ 54
5.1.3 LUTITIUM 177 Parameters evaluation ................................................ 55
5.1.4 Comparison of quality control and dosimetry facilities for 18 FDG, and
Gallium 68,Lutitium 177 at INMOL Hospital with respect to IAEA standard
specifications........................................................................................................ 56
5.2 Discussions .................................................................................................... 58
5.2.1 Good manufacturing practice ................................................................. 58
5.2.2 Regulatory aspects of PET radiopharmaceuticals in the USA and
EUROPE .............................................................................................................. 60
USA regulatory view............................................................................................ 60
European regulatory view .................................................................................... 61
5.2.3 Quality aspects of PET radiopharmaceuticals ....................................... 61
5.3 Guidelines...................................................................................................... 63
Appendix ...................................................................................................................... 73
6 Radioisotope Properties ....................................................................................... 73
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6.1 LABELLING EFFICIENCY ........................................................................ 75
6.2 Biokinetics and biodistribution studies for Radiopharmaceutical................. 76
6.3 RADIOTOXICITY STUDIES ...................................................................... 77
6.4 Drug Handling AND Patient Preparation...................................................... 78
7 Patient Dosimetry................................................................................................. 80
7.1 Work load ...................................................................................................... 80
8 Clinical trial studies ............................................................................................. 81
9 Equipment and Instrumentation Compatibility and Quality Control ................. 83
9.1 Medical Staff Competence ............................................................................ 86
9.2 Economical and Commercial Analysis of Radiopharmaceutical ................. 87
9.3 STORAGE, HANDLING and Radiation Protection .................................... 88
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List of Figures
Figure 1-0-1 dosimetry of therapeutic and diagnostic radiopharmaceuticals ............. 14

Figure 5-1 FDG18 ........................................................................................................ 53
Figure 5-2 Gallium 68 parameters evaluation ............................................................. 55
Figure 5-3: Lutitium 177 parameters evaluation ......................................................... 56
Figure 5-4 : Comparison of quality control and dosimetry facilities for 18 FDG, AND
GALLIUM 68,LUTITIUM 177, at INMOL HOSPITAL ........................................... 57
Figure 5-5 evaluation of radiopharmaceuticals with comparative specifications and
acceptance criteria of parameters ................................................................................. 58
Figure 5-6 inter connection of QA ,GMP,Production and QC .................................... 62
xii
List of Tables
Table 2-1 Lutetium (177Lu) principle radiation emission data 22
Table 2-2 Quality Control Tests for 177 Lu Prepared via both Pathways 23
Table 2-3 Quality Control Tests for 68Ga From 68Ge/68Ga Generator Eluted with
Dilute Hydrochloric Acid 27
Table 2-4 The List Of The Tests Performed, Methods And Specifications (Acceptance
Criteria) Recommended For Cyclotron Produced 68Ga 29
Table 2-5 Quality Control Tests are recommended for 213 Bi 30
4-1 FDG18 quality control specifications according to European Pharmacopoiea 51
Table 5-1 18FDG parameters evaluation 53
Table 5-2 Gallium 68 parameters evaluation 54
Table 5-3: Lutitium 177 parameters evaluation 55
Table 5-4 evaluation of radiopharmaceuticals with comparative specifications and
acceptance criteria of parameters 56
Table 5-5 evaluation of radiopharmaceuticals with comparative specifications and
acceptance criteria of parameters 57
xiii
Abstract
Iqra Anwar, Ms Medical Physics, Department of Physics and Applied Mathematics,
PIEAS, Islamabad 45650, Pakistan, Evaluation of Implementation of Standard
Requirements on Clinical Use of New Radiopharmaceutical, Supervised by, “ Dr.
Muhammad Shahid”, May, 2019.
AIMS: New radioisotopes that are currently practiced for clinical use include
67
Ga, Cu, 111In, 90Y and 177Lu etc. There are different pros and cons associated with
64
their use. Besides, radiopharmaceuticals containing radionuclides of short physical

half-life (e.g. PET radiopharmaceuticals (11C, 68Ga) are usually released for use before
quality tests are finished while they need special attention on purity and control
methods in synthesis and purification. The radiotoxicity of new radionuclides in the
body is associated with the decay characteristics of the radionuclide as well as its
residence time in the body. These factors contribute in patient dose. Furthermore, the
science and radiopharmaceutical industry is evolving so there is a need to modify the
regulatory requirements accordingly. This study was carried out at a nuclear medical
center where we observed novel radioisotopes and pharmaceuticals that use or intend
to use for diagnostic or therapeutic applications. The implementation of the regulatory
requirements in the production, control, quality assurance and medical application of
locally produced radioisotopes was also observed. The study revealed that available
radioisotopes and radiopharmaceuticals are used in safe and effective manner for
defined procedures however, in minor improvements are needed to bring the practices
according to international standards.
xiv
1 Introduction
1.1 Radiopharmaceuticals
Radiopharmaceuticals are radiolabelled compounds designed to deliver

diagnostic information as a result of which they are incorporated into selected cellular
targets. These delicate molecular tools are essential components of nuclear medicine
technology and must be prepared prior to administration to the patient (IAEA-
TECDOC--1782). Radiopharmaceuticals are pharmaceutical formulations consisted
of radioactive substances i.e. radioisotopes and molecules labeled with radioisotopes,
intending their use either in diagnosis or therapy (WHO Monograph).
Radioprmaceuticals are biologically active molecules labeled
by radionuclide which provide a beneficial source of ionizing radiation mainly
applied in diagnostic imaging and therapy (Khalil, et. al., 2011). Mainly, they are
administered by the intravenous route. In some rare cases, the same element (e.g. the
diagnostic radionuclide 64Cu and the therapeutic radionuclide 67Cu) or even the same
radionuclide (e.g. 131I) is used for both purposes (Macey, D. J., 2001). Radio
diagnostic imaging is a rapid, non-invasive procedure. A radiopharmaceutical is a
radioactive compound used for the diagnosis and therapeutic treatment of human
diseases. (Burns, H. D., 1978).
1.1.1 Mechanism of action

Radiopharmaceutical has two components: a radionuclide and a
pharmaceutical. In designing a radiopharmaceutical, a pharmaceutical is first chosen
on the basis of preferentialed localization in a given organ or its contribution in the
physiological function of the organ. Then a suitable radionuclide is tagged onto the
chosen pharmaceutical such that after administration of the radiopharmaceutical,
radiations emitted from it are detected by a radiation detector (Mayur, P., et. al.,
2001).
Nuclear medicine is mainly based on two powerful, well-established imaging
tools; single photon emission computed tomography (SPECT) and positron emission
tomography (PET). In SPECT, γ emissions, releasing energy between 30 and
1
300 keV, from the administered radiopharmaceutical are detected by a γ camera,
allowing visualizing the origin of the rays that depends on how an organ is
functioning (Van Eldik, R., & Hubbard, C. D. (2016).
PET exploits a radiopharmaceutical labeled with a positron emitting isotope.
After a short distance, the emitted β+ particle undergoes annihilation with an electron
by producing a couple of 511 keV γ rays that travel in opposite directions and are then
detected by a ring of detectors (Mayur, P., et. al., 2001)
Radiopharmaceuticals are the preferred agents for the assessment of function,
as opposed to structure (Van Eldik, R., & Hubbard, C. D. (2016). The availability and
cost of the radionuclide is an important factor. In addition, an acceptable nuclear
decay of the specific radionuclide, a physical half-life conducive to
radiopharmaceutical preparation and tumor pharmacokinetics, fairly rapid and stable
attachment of the radionuclide to the desired chemical species and appropriate gamma
ray emissions for imaging to aid in biodistribution and imaging are important
(Zimmer, A. M., Director, N. P., & Officer, R. S. (2004).
1.2 Clinical uses of Radiopharmaceuticals

Radiopharmaceutical therapy (RPT) involves the use of radionuclides that are
either conjugated to tumor-targeting agents (e.g., nanoscale constructs, antibodies,
peptides, and small molecules) or concentrated in tissue through natural physiological
mechanisms that occur predominantly in neoplastic or otherwise targeted cells (e.g.,
Graves disease) (Sgouros, G., 2019). The ability to collect pharmacokinetic data by
imaging and use this to perform dosimetry calculations for treatment planning
distinguishes RPT? from other systemic treatment modalities. Treatment planning has
not been widely adopted, in part, because early attempts to relate dosimetry to
outcome were not successful. This was partially because a dosimetry methodology
appropriate to risk evaluation rather than efficacy and toxicity was being applied to
RPT?
The weakest links in both diagnostic and therapeutic dosimetry are the
accuracy of the input and the reliability of the radiobiological models used to convert
dosimetric data to the relevant biologic end points. Dosimetry for RPT places a
greater demand on both of these weak links. To date, most dosimetric studies have
been retrospective, with a focus on tumor dose-response correlations rather than
prospective treatment planning (Sgouros, G., 2019).
2
1.3 Dosimetry of Radiopharmaceuticals
Internal Radiation Dosimetry To assess the effects of radiation on a living
organ, it is important to understand and quantify radiation energy deposited and
absorbed by that organ. This deposition/absorption of energy is called radiation
absorbed dose. Internal radiation dosimetry involves the studying of energy absorbed
by the organs from an internally deposited radionuclide. It includes the study of
physical characteristics of radionuclides, pharmacokinetics and biokinetics of the
radiopharmaceutical, as well as establishing assumptions and models for calculating
absorbed radiation energy (Zhu, X. (2006).
Radiopharmaceuticals are widely used for diagnostic imaging and radiation
therapy. Although radiation therapy uses damage to living tissue to the advantage of
the patient, this damage, however, is a limitation for the diagnostic application.
Radiation dosages for specific indications are optimized based on thorough studies
performed on animals and through clinical trials on human subjects prior to approval
for clinical applications. Proper dosages are derived through careful study of
pharmacokinetics, the physical characteristics of the radionuclide, metabolism of the
subject, and the pharmacodynamics of the radiopharmaceutical in animal and human
subjects (Zhu, X. (2006).
The chemical- and radiotoxicities and adverse reactions are well understood
before an optimal and safe dosage is recommended. Doses are typically scaled by
weight, or total body surface area, and reduced for children. The recommended
dosage for a specific indication and route of administration are stated by the drug
manufacturers in the package insert, and are readily available online. To assess the
effects of radiation on a living organ, it is important to understand and quantify
radiation energy deposited and absorbed by that organ. This deposition/absorption of
energy is called radiation absorbed dose. Internal radiation dosimetry involves the
studying of energy absorbed by the organs from an internally deposited radionuclide.
It includes the study of physical characteristics of radionuclides, pharmacokinetics
and biokinetics of the radiopharmaceutical, as well as establishing assumptions and
models for calculating absorbed radiation energy (Zhu, X. (2006).
Dosimetry for therapeutic agents is not fundamentally different than for
diagnostic agents. It is possible that one may wish to calculate dose to a tumor
volume, in addition to the doses calculated to the usual organs and tissues of the body
(Stabin, M. (2006). Tumor ROIs may be drawn just as any organ ROI is drawn, with
3
conjugate view imaging methods applied to estimate the activity in the tumor mass as
a function of time and the time-integral of activity (Stabin, M. (2006).
Once the number of disintegrations is known, tumor self-dose may be obtained
using absorbed fractions and dose factors from a number of publications that have
treated energy absorption in unitdensity spheres or ellipsoids of different
sizes.18192021 The OLINDA/EXM code1 uses the absorbed fractions of Ref. 13 and
provides tumor self-dose factors and doses, given entry of the number of
disintegrations assumed to occur within the unit-density sphere., as the values. A safer
practice is to fit the values to a polynomial or multiple exponential functions and
calculate the intermediate values from the function (Stabin, M. (2006).
Also, it is common in cancer patients to encounter organs that are notably
different than the standard models, due to the disease and/or complication.To perform
this calculation, you must isolate the values for penetrating and nonpenetrating
emissions, multiply them by these new absorbed fractions, and then recalculate the
total dose by adding the two components together. Fortunately, the OLINDA/EXM
code1 performs this calculation automatically for the user, given entry of the new
organ mass of interest (Stabin, M. (2006).
1.3.1 Internal dosimetry is helpful to

• Assess patient dose in nuclear medicine.
• Define guidance/reference levels in NM.
• Permit the use of new radiopharmaceutical.
• Plan radionuclide dose (therapeutic).
• Set investigation levels in a radiation area.
• Decide radionuclide discharge limits (health physics).
• Determine dose in accidental situation.
• Measure dose due to radio-contaminants or impurities.
• Develop regulatory/working guidelines/procedures.
• Define patient discharge limits.
1.3.2 Dosimetric systems

• Marinelli/Quimby Method to assess the dose from a beta emitter.
• The International Commission on Radiological Protection (ICRP) to use in
protecting radiation workers.
4
• Medical Internal Radiation Dose System (MIRD) to use in estimating
radiation dose of patient.
• Radiation Dose Assessment Resource (RADAR) electronic resource for dose
quantities and data.
• Equivalent Dose (Sv) = Absorbed Dose X Quality Factor (Q) to reflect
biological effect.
• Effective Dose (Sv)= Absorbed Dose X Tissue Weighting Factor (w ).
R
1.4 Quality control of Radiopharmaceuticals
Radiopharmaceuticals are the preferred agents for the assessment of function,

as opposed to structure. The availability and cost of the radionuclide is an important
factor. In addition, an acceptable nuclear decay of the specific radionuclide, a physical
half-life conducive to radiopharmaceutical preparation and tumor pharmacokinetics,
fairly rapid and stable attachment of the radionuclide to the desired chemical species
and appropriate gamma ray emissions for imaging to aid in biodistribution and
imaging are important. (Zimmer, A. M., Director, N. P., & Officer, R. S. (2004).
Radiopharmaceuticals consist of pharmaceutical component as well as
radioactive component so a strict requirement exists to fulfil the quality specifications
for both of them. - Radiochemical Purity - Radionuclidic Purity - Radio assay -
Organoleptic Properties - Sterility - pH - Apyrogenicity - Chemical purity etc. It is a
wide term commonly used for the confirmation and validity of various ways and
measurements adopted to obtain a high quality procedure for intended use with
guaranteed performance. Biological quality control of pharmaceutical products
becomes essential as they are ultimately to be consumed by living organisms
(Khurshid, S. J., & Sadiq, M. Z. (1996). There are two main factors by which the level
of quality of a radiopharmaceutical may be established: (a) By setting a standard (b)
By the manufacturing process (IAEA, Technical Report Series,)
In addition to radiation issue, short halflives of these positron emitters (78
sec~110 min) 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
pharmaceutical industry. Hence, commercial large-scale manufacturing and small-
scale preparation of PET radiopharmaceuticals are respectively allowed in
5
radiopharmaceutical industries and the radiopharmacy of hospitals in most countries
worldwide. Because of short half-lives of PET radiopharmaceuticals, a QC test 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 (Huang, Y. Y. (2018).
In the world it is not mandatory to follow FDA regulations. quality
requirements for starting materials of radiolabelled drug substances (radiolabelled
active ingredients) quality requirements for active ingredients of radiopharmaceuticals
and minimal range of toxicological data, – dosimetry data.perform at least one test to
verify the identity of each batch of material – check the certificate of analysis
including: – Identification – Chemical purity – Stability data – Storage conditions
,Expiry or re-qualification date , Batch identity – Impurity profile (Verbruggen, A., et,
al., 2008).
Toxicology Studies to Support the FIH Therapeutic Phase Sponsors should
evaluate both radiation- and ligand-related toxicities. Such evaluations can be through
toxicology studies or biodistribution studies, as appropriate. Generally no toxicity
studies are warranted before a FIH study when the radiopharmaceutical is a neat
radionuclide (i.e., contains no ligand). Toxicities of the radiopharmaceutical are from
the radionuclide decay, and thus, the results of the animal biodistribution and
dosimetry study with added safety endpoints can be used to determine short-term
radiation-related toxicities. Below are recommendations for radiation- and ligand-
related safety assessment (Isotop, R. (2013).
Evaluation of radiation-induced toxicity: The animal biodistribution and
dosimetry studies, together with the general knowledge of organ-specific radiation-
induced toxicities, are usually sufficient to address toxicities from the radiation.
Published articles on organ-specific radiation-induced toxicities should be included in
the submission (Isotop, R. (2013).
Sponsors should consider the addition of safety endpoints, such as clinical
signs, body weight (BW), hematology, and serum chemistry, into the design of the
biodistribution study. To identify any ligand-related toxicity, sponsors should conduct
a general toxicology study with the cold pharmaceutical in a relevant species before
initiation of a FIH study. Ligand-related toxicities have been observed but are usually
minor compared with radiation-induced toxicities, and hence, a study in one species is
6
generally considered sufficient. Unless otherwise justified, the species selected for
toxicology study should be the same as the species used for animal biodistribution and
dosimetry study. Frequency of administration in the toxicology study should follow
recommendations in the ICH guidance for industry Nonclinical Evaluation for
Anticancer Pharmaceuticals and should take into account the frequency of
administration in the FIH trial (both the human biodistribution and dosimetry and the
therapeutic phase that follows it).
Long-Term Toxicity Assessments to Support Marketing in general, the
nonclinical data and the clinical phase 1 data should be sufficient for moving to phase
2. Sponsors should conduct long-term toxicity assessment studies to support
marketing, and the results should be submitted with the marketing application. These
studies should assess both ligand- and radiation-related toxicities. The dosing period
in animals can follow ICH S9. For most pharmaceuticals intended for the treatment of
patients with advanced cancer, nonclinical studies of 3 months’ duration are
considered sufficient to support marketing. Below are recommendations for study
design and circumstances when studies may not be needed (ICH, G. (2009). Contains
Nonbinding Recommendations Draft — Not for Implementation Evaluation of ligand-
induced toxicity:
Chronic toxicity studies of the cold pharmaceutical may not be needed in
several circumstances: when a limited number of doses are administered to patients
(e.g., two or three doses), when the ligand is for delivery purposes only and
administration will result in a small dose (e.g., in microgram ranges), or when the cold
pharmaceutical has a short half-life and dosing frequency is low (e.g., every 4 to 8
weeks).
On the other hand when a chronic study is needed, a study in a single species
is generally considered sufficient. This study can be combined with the late radiation
toxicity study. An assessment of late radiation toxicities is warranted when patients
have a long life expectancy that could be affected by late radiation adverse effects.
For recommendations on animal study design and endpoints, see the guidance for
industry Nonclinical
Evaluation of Late Radiation Toxicity of Therapeutic Radiopharmaceuticals.
Identification of a no observed adverse effect level is not needed. The study in a
single species is generally considered sufficient. When a limited number of organs is
7
examined by histopathology, the organs selected should be justified. Any organs with
gross pathology finding should be examined microscopically (Wang, J., et. al., 2004).
B. Genotoxicity, Reproductive Toxicology, and Carcinogenicity Studies. No
genetic or reproductive toxicity or carcinogenicity study with the radiopharmaceutical
or the cold pharmaceutical is warranted during drug development or for approval.
Alpha, beta, and gamma radiation cause deoxyribonucleic acid damage and are
inherently genotoxic and carcinogenic, and damage male and female germ cells and a
developing conceptus. These risks should be communicated in product labeling (see
section VII., Labeling Recommendations(Wang, J., et. al., 2004).
1.5 Dosimetry of radiopharmaceuticals

Dosimetry for diagnostic procedures utilized in nuclear medicine;
Dosimetry for therapeutic procedures (radionuclide therapy); Dosimetry in
conjunction with accidental intake of radionuclides. To optimize the procedure
concerning radiation protection consistent with an accurate diagnostic test. The mean
pharmacokinetics for the radiopharmaceutical should be utilized for the calculation of
the time-integrated activity and S values based on a reference man phantom.
Absorbed dose / injected activity for most radiopharmaceuticals used for diagnostic
procedures are in ICRP 53, updates in ICRP 80 and ICRP 106 (Alexander, G. A., et.
al., 2007).
To optimize the treatment so as to achieve the highest possible absorbed dose
to the tumour, consistent with absorbed dose limiting toxicities. Individualized
treatment planning should be performed that takes into account the patient specific
pharmacokinetics and biodistribution of the therapeutic agent (Lentz, F., et, al., 2009).
OLINDA/EXM: Organ Level Internal Dose Assessment/exponential
modelling. Software for the calculation of absorbed dose to different organs in the
body, being MIRDOSE 3.1 its predecessor. OLINDA/EXM also includes a module
for biokinetic analysis, allowing the user to fit an exponential equation to the data
entered on the activity in an organ at different time points. S values can be found on
MIRD Pamphlet No. 11 ,in the OLINDA/EXM software, on the RADAR web site and
are scaled by mass, allowing for a more patient specific dosimetry (Bailey, D. L., et,
al., 2016). Owing to the inverse relation between the absorbed dose and the mass of
the target region, scaling can have a considerable influence on the result.
Alternatively, it was suggested to scale the S values to the total mass of the patient,
8
assuming that the organ size follows the total body mass. The lean body weight
should be used to avoid unrealistic organ mass values (S values due to obese or very
lean patients (Nuclear Medicine Physics: A Handbook for Teachers and Students –
Chapter 18)
1.6 Dosimetry Quantities and Units

Quantification of the amount of radiation received by a potentially
radiosensitive site is essential to the characterization of the possible risks of the
exposure. The principal quantity used to identify and measure the amount of radiation
received is the absorbed dose (Rana, S., Kumar, R., Sultana, S., & Sharma, R. K.
(2010).
Absorbed dose is the energy absorbed per unit mass of any material. Absorbed dose
(D) is defined as:
D = dE/dm
Where dE is the mean energy imparted by ionizing radiation to matter in a
volume element of mass dm. The units of absorbed dose are energy/mass of any
material. One may use, for example, erg/g, J/kg, or others. Special units are also
defined for absorbed dose: 1 rad = 100 erg/g 1 gray (Gy) = 1 J/kg 1 Gy = 100 rad.
Equivalent dose is the absorbed dose modified by a factor accounting for the
effectiveness of the radiation in producing biological damage. Equivalent dose H is
the dose delivered by radiation type R averaged over a tissue or organ T, and wR is
the radiation weighting factor for radiation type R.; the fundamental units of
equivalent z (Avasthi, D. K., & Mehta, G. K. (2011).
1.7 Medical Internal Radiation Dose System

The MIRD system was developed primarily for use in estimating radiation
doses received by patients from administered radiopharmaceuticals; it was not
intended to be applied to a system of dose limitation for workers. To learn internal
dosimetry for radiopharmaceuticals, Dr. Carol Marcus said that she “ took the Great
Red Pamphlets home and began learning from them.”9 These “great red pamphlets”
of the MIRD system indeed defined the methods, equations, and models for nuclear
medicine dosimetry for many years (Lyra, M. E., et, al., 2013). A listing of selected
MIRD pamphlets is given in Table 2.2.
9
1.8 RAdiation Dose Assessment Resource (RADAR)
In the early 21st century, an electronic resource was established on the Internet
to provide rapid, worldwide dissemination of important dose quantities and data. The
RAdiation Dose Assessment Resource (RADAR) established a Web site
(www.doseinfo-radar.com) and provided a number of publications on the data and
methods used in this system.
The RADAR system10 has perhaps the simplest representation of the
cumulative dose equation: D = N × DF where N is the number of disintegrations that
occur in a source organ, and DF is DF = k i yiEii m 2. The DF is conceptually similar
to the “S value” defined in the MIRD system. The number of disintegrations is the
integral of a time-activity curve for a source region. RADAR members produced
compendia of decay data, dose conversion factors, and catalogued standardized dose
models for radiation workers and nuclear medicine patients, among other resources.
They also produced the widely used OLINDA/EXM11 personal computer software
code, which used the equations shown here and the input data from the RADAR site.
This code was basically a revised version of the highly popular MIRDOSE12
software, which implemented the MIRD method for internal dose calculations (but
was not in any way associated with the MIRD Committee itself).
The RADAR site and OLINDA/EXM software implement all of the most
current and widely accepted models and methods for internal dose calculations and
are constantly updated to reflect changes that occur in the science of internal dose
assessment. RADAR is now an officially sanctioned committee, like MIRD and the
ICRP, and its members have published a number of documents, data sets, and tools
with a literature basis that is clearly important to the current practice of dosimetry.
1.8.1 Usefulness of the Dosimetry Systems

Any of the systems above will give useful estimates of absorbed dose,
assuming that good input data is provided to the system and assuming that appropriate
models are employed for the dose conversion factors. The choice of a particular
system is based on practicality and applicability. Most of the results in the ICRP
systems are oriented toward protection of radiation workers, whereas those of the
MIRD system are oriented towards nuclear medicine patients. The RADAR system is
designed to accommodate either. Further, the RADAR system has been implemented
10
in automated electronic methods that have group, sanctioned by the Society of
Nuclear Medicine. Others regularly use the RADAR system, due to its convenience
and wide acceptance (Van Dyk, J., et, al., 1993).
1.9 Models and Resources for Internal Dose

Calculations Standardized
Models for Dosimetry Reliable estimates of radiation dose from the use of
diagnostic or therapeutic radiopharmaceuticals in nuclear medicine are essential to the
evaluation of the risks and benefits of their use. To estimate absorbed dose for all
significant tissues, one must determine for each tissue the quantity absorbed dose,
which is the amount of energy from ionizing absorbed per unit mass of any material.
Here our interest is in the dose to human tissues. One may also calculate equivalent
dose, which includes terms describing the effectiveness of different radiations in
producing biological damage in human tissues. It is important that investigators use
standardized methods, models, and tools for the calculation of absorbed doses, so that
other researchers, users, regulators, and others can readily understand and (if desired)
reproduce the calculations.
1.10 Input Data for Dose Calculations

The input data needed for a numerical solution of the equations above include three
major components:
1. Decay data for the radionuclide
2. Biokinetic data for the radiopharmaceutical under study ( i and Te values).
3. Absorbed fractions () for different radiations and all source and target regions of
interest.
4. Masses of the target regions
5.Choice and Application of Standardized Models
Internal Dose Calculation
Input Data: Animal or Human Studies
Collection of Data
on data gathering and quantification for dosimetry to determine the activity-time
profile of the radioactivity in source regions, four questions need to be answered:
1. What regions are source regions?
2. How fast does the radioactivity accumulate in these source regions?
11
3. How long does the activity remain in the source regions?
4. How much activity is in the source regions? (Stabin,2004)
1.10.1 Extrapolation of Animal Data

In an animal study, the compound of interest may be administered to a
number of animals that are then sacrificed at different times, with the activity within
the organs estimated by counting: harvesting the organs and counting them in a well
counter or other device, or, perhaps, using autoradiography techniques on excised
tissue samples, or imaging of the animals (e.g., with a microPET or microSPECT
imaging system). The data gathered must be used to predict uptakes in the human
from the concentrations seen in the animal tissues (extrapolation). Extrapolation of
animal data to humans is by no means an exact science (Stabin, M. G., & Mihailidis,
D. N. (2009).
Image Quantification: Human Data The external conjugate view counting
pair (anterior/ posterior) method is the approach most frequently used to obtain
quantitative data in human studies for dosimetry. In this method, the source activity
Aj is given as3: Aj = IAIP e−et fj C fj ≡ jtj/2 sinhjtj/2 where IA and IP are the
observed counts over a given time for a given region of interest (ROI) in the anterior
and posterior projections (counts/time), t is the patient thickness over the ROI, e is the
effective linear attenuation coefficient for the radionuclide, camera, and collimator, C
is the system calibration factor (counts/time per unit activity), and the factor f
represents a correction for the source region attenuation coefficient (j) and source
thickness (tj) (i.e., source self-attenuation correction). (Stabin, M. G., & Mihailidis, D.
N. (2009). This expression assumes that the views are perfectly collimated (i.e., they
are oriented toward each other without offset) and assumes a narrow beam geometry
without significant scattered,
Corrections for Scattered Radiation
Corrections for Background Activity
Correction for Overlapping Organs and Regions
Obtaining Gamma Camera System Attenuation and Calibration Coefficients
Attenuation Coefficient
System Calibration Factor As with the attenuation coefficient, the system calibration
factor, C, must be measured at some time before or after radiopharmaceutical
administration in a separate experiment. For this factor, the method is to prepare a
12
standard of known activity of the same radionuclide to be used for admini stration to
subjects, usually a few tens of MBq in a suitable container.
• Kinetic Analysis Analysis of Kinetic Data
• Direct Integration method
• Least-Squares Analysis
• Trapezoidal Method and Least-Squares Analysis Compared
• Compartmental Models
• Dose Calculations
After one is satisfied with the adequacy of the kinetic data gathered and has
performed a kinetic analysis (and thus has estimates of the numbers of disintegrations
occurring in each of the important source organs in the body), the final step in the
process is to combine the time-activity integrals with the appropriate dose conversion
factors, , in order to produce dose calculations for the individual organs that consider
contributions from all of the source regions. This can be done by hand or using
various mathematical tools, such as spreadsheets, mathematical tools implemented on
personal computers or calculators, or software programs specifically designed to
calculate.
• Calculation of S Value for Average Organ Dose
• Dose to One Organ
• Dose to More than One Organ
• Dose to the Fetus, with Remainder of Body Correction
• Dose to Several Organs
• Correction of Hollow Organ Dose if Source Is in the Wall
• Effective Dose
• Image-Based, Patient-Individualized Dosimetry
• Animal Data Set for a radionuclide-Labeled Emitter, No Excretions
• Animal Data Set for a radionuclide-Labeled Emitter, Urinary Excretion
• Animal Data Set for a radionuclide-Labeled Emitter, Urinary and Fecal
Excretion
• Case with Ascites
13
Figure 1-0-1 dosimetry of therapeutic and diagnostic radiopharmaceuticals
1.10.2 Biological endpoints
On the other hand, very recent research has profoundly challenged

conventional notions of the relationship between radiation dose and observed effects.
In a report by the American Association of Physicists in Medicine (AAPM), it is
noted that various cellular and organ studies have shown that low-LET-type effects
have been seen when Auger emitters are present only in the cytoplasm of cells,
whereas when Auger emitters may be incorporated into the DNA of cells, the
resulting survival curves are similar to those normally seen for high-LET alpha
particles. Biological Effects of Radiation. Also, in some in vivo studies with
radioprotectors, the intense local damage imparted to cells by Auger emissions has
been shown to be able to be mitigated somewhat even though the high-LET-type
effects are known to be present (Stabin, M. G. (2008). The committee reached the
rather unsettling conclusion that the absorbed dose from Auger emitters must be
calculated at a level suited to the biological system employed. Hence, a number of
target volumes are of interest:
• individual strands or bases of the DNA molecule
• supercoiled DNA
14
• cell or cell nucleus
• bulk tissue
Choosing the target volume, however, is complex. The radiation properties of
the radionuclide certainly play a role in this regard. Just as important is the
distribution of the radioactivity within the cells, which in turn depends on the
chemical nature of the radiocompound. Hence, the appropriate target volume must be
determined on a case-by-case basis. [emphasis added.]† The group ultimately
concluded that a value of 10 be used for the radiation weighting factor (wR) for
predicting therapeutic outcome if an Auger emitter is used that is thought to be
covalently bound to the DNA of the cells treated. If the emitter, conversely, is
localized in the nucleus, but not covalently bound to DNA, a weighting factor of 5
was recommended (Stabin, M. G. (2008).
Brooks points out that absorbed dose is often used too liberally as a direct
indicator of radiation risk.12 Whereas the simple concept of energy absorbed per unit
mass of tissue has good predictive value at some dose levels and if activity is
uniformly distributed throughout an organ (in the case of internal emitters), it is
clearly not a good predictor of biological response when activity is not uniformly
distributed †Excerpt reprinted with permission from Humm, J., et al. “Dosimetry of
Auger-electron-emitting radionuclides: Report No. 3 of AAPM Nuclear Task Group
No. 6a.” Medical Physics 21, 2004; 1994. of when energy deposited by high LET
particles occurs in regions where it is difficult to distribute the energy over the
appropriate target mass .
Recent experimental evidence has shown that energy distribution alone cannot
always predict the occurrence of cellular changes, but that in some conditions, cells
with no direct energy deposition from radiation may demonstrate a response (the
bystander effect). Brooks notes that “The potential for bystander effects may impact
risk from nonuniform distribution of dose or energy in tissues and raises some very
interesting questions as to the validity of such calculations.” Hall notes that “The
plethora of data now available concerning the bystander effect fall into two quite
separate categories, and it is not certain that the two groups of experiments are
addressing the same phenomenon.” Those two categories are Medium transfer
experiments:. Microbeam irradiation experiments: Experiments suggest that bystander
effects are limited to the organ irradiated and have been demonstrated primarily in
15
experiments with alpha particles. These results challenge the traditional notion of the
relationship of dose and effects.
Another mechanism, called genomic instability, also suggests that the effects
from radiation may be felt in cells other than those directly irradiated. Cells irradiated
with radiation have been shown to not have observable radiation damage, but
subsequent generations of these cells may show DNA damage. Morgan notes that,
while genomic instability has been demonstrated in vitro and in vivo, some results are
conflicting, and interpretation remains controversial. Morgan states that “Because
radiation risk estimates are also organ specific, it is reasonable to assume that any
bystander effect induced in vivo is accounted for in models of organ risk evaluation.
As a result, it is unlikely that the resurgence of interest in these non-targeted radiation
effects will substantially alter risk estimates.”
16
Chapter 2
2 Novel Radiopharmaceuticals
There is a clear need for the introduction into clinical use of new PET and
SPECT radiopharmaceuticals, which could exploit the limitations of existing tracers
and take advantage of a more in-depth knowledge of cancer cell biology. New PET
and SPECT radiotracers would also be of benefit in the diagnostic evaluation of heart
and brain diseases. There is also a rapidly growing interest in tracers that are aimed at
diagnosing infectious and inflammatory diseases.
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 (AlJammaz, I. (2009).
11
The most common radionuclides for PET radiopharmaceuticals include C,
15
O, 13N, 18F, 68Ga (overview of pet radiopharmaceuticals) grown because of advances
in technology, including hybrid imaging, the introduction of new
radiopharmaceuticals for diagnosis and therapy, and the development of molecular
imaging based on the tracer principle. The development of molecular radio-therapy,
Continued growth of the field will require cost-effectiveness data and evidence that
nuclear medicine procedures affect patients outcomes (AlJammaz, I. (2009).
Much of the science for production of the next generation of targeted radio-
pharmaceuticals has been demonstrated. Basic chemical advances in labeling
molecules at high levels of radioactivity have allowed assessment of the therapeutic
potential of alpha-emitting radionuclides in preclinical models and in human patients.
Alpha particles are higher energy (usually 5-8 MeV) and shorter range (usually 50–80
microns—just a few cell diameters). Beta particles are lower energy (usually 0.1–1
MeV) and longer range (usually 1–10 millimeters) (Ramogida, C. F., & Orvig, C.
(2013).
Values are taken from Advancing Nuclear Medicine Through Innovation
(Natl. Academies Press). The higher energy and shorter range of alpha- emitters gives
them their localized potent cytotoxicity .
17
Table 2.1: some novel radiopharmaceuticals with their principle emissions and
applications
Radionuclide Type of Isotopic half- Example use

emission life
11
C (carbon) β+ 20.4 min PET imaging
18
F (fluorine) β+ 109.8 min PET imaging
64
Cu (copper) β+, β, EC 12.7 hrs PET imaging
68
Ga (gallium) β+ 68 min PET imaging
177
Lu (lutetium) strong β− 6.7 days PotentiaL
Therapeutic
225
Ac Α 10 days Localized killing,
(actinium) potential therapeutic
11
2.1 Radionuclide C
• Half-life 20 min
• Max specific activity (Ci/ µmol) 9220
• ß + (%) 99
• Max Eß (MeV) 0.96
• Max ß+ range (mm) 4.1
• Production route Cyclotron
2.2 Radionuclide 15O

• Half-life 123 sec
• Max specific activity (Ci/ µmol) 90,800
• ß + (%) 100
• Max Eß (MeV ) 1.19
18
2.3 Radionuclide 13N
• Max specific activity (Ci/ µmol) 18,900
• ß + (%) 100
2.4 Production and Demand of Radioisotopes

The production of radionuclides for use in medicine, both in diagnosis and
therapy, is carried out using several routes. In most cases, nuclear production facilities
such as nuclear reactors as well as cyclotrons are required. Reactor-produced
radionuclides are generally neutron-rich nuclides. They mostly decay by β− emission
produced radionuclides, on the other hand, are often neutron deficient and decay
mainly by EC or β+ emission (Rösch, F. (2013).
In parallel, nuclear reactors and cyclotrons also produce radionuclides
decaying by the emission of β− and Auger or conversion electrons and alpha particles,
relevant to endoradiotherapy. Compared to direct nuclear production reaction, in a
limited number of cases non-direct production routes are available using radionuclide
generator systems. The following three subsections separately describe the production
of radionuclides relevant to life sciences using (i) nuclear reactors, (ii) particle
accelerators and (iii) generator systems (Rösch, F. (2013).
The isotope production programme involves several interrelated activities such
as target fabrication, irradiation in reactor or accelerator, transportation of irradiated
target to radioactive laboratory, radiochemical processing or encapsulation in sealed
source, quality control and transportation to end users. Each step needs experts from
respective disciplines, laboratory facilities equipped for radioactivity handling and
other supporting infrastructure. (IAEA, 1340)
2.5 Locally produced

18FDG:
19
2.5.1 Radionuclide 18F
• ß + (%) 97
• Max Eß (MeV ) 0.635
2.6 Imported
LUTITIUM 177, GALLIUM 68
2.7 Intended to Buy

ACTINIUM 225, ZIRCONIUM 89, YUTTRIUM 90, COPPER 64,OXYGEN
15,NITROGEN13, CARBON 11
2.8 LUTITIUM 177

2.8.1 Production
177 176
Lu can be “directly” produced by irradiation of Lu enriched targets in
177
many reactors operating in different parts of the world, the Lu specific activity can
vary significantly depending on the specific reactor neutron flux and irradiation
conditions. However, no carrier added (NCA) 177Lu can be produced in most reactors
176
by following an ‘indirect’ method by irradiating enriched Yb targets at a neutron
177
flux of 1013 to 1015 n.cm-2.s-1 and the Lu produced will be usable for all
applications, irrespective of the neutron flux in the reactor and irradiation conditions.
176
In this ‘indirect’ method of production, the isotopically enriched Yb target
undergoes an (n,) reaction to produce 177Yb which subsequently decays by - emission
177 177
(T = 1.9 h) to yield Lu. The Lu produced by the ‘indirect’ route should have a
specific activity close to the theoretical value of 110 Ci/mg. However, the “indirect”
method has significantly lower production yields due to the low thermal neutron
activation cross section, which will depend on the thermal neutron flux of the reactor.
176
Because of the low Yb(n,)177Yb neutron cross section, large quantities of the
176
enriched Yb target will thus be required and very efficient Lu/Yb separation
chemistry is required, The process also generates radioactive waste.
177
All these factors together will make NCA Lu significantly more expensive
177 176
than the Lu produced by ‘direct’ method by activating enriched Lu targets.(
20
177
Indirect Production of No Carrier Added (NCA) Lu from Irradiation of Enriched
176
Yb: Options for Ytterbium/Lutetium Separation (Dash, A., Chakravarty, R., F Russ
Knapp, F., & MR Pillai, A. (2015).
2.8.2 Decay Characteristics

177
Lu is a radioisotope having very good potential for use in in vivo therapy,
177
because of its favourable decay characteristics. Lu decays witha half-life of 6.71 d
by emission of beta particles with Emax of 497 keV (78.6%), 384 keV (9.1%) and
176 keV (12.2%) to stable 177Hf. It also emits gamma photons of 113 keV (6.4%) and
208 keV (11%) (Firestone, 1996)
Lutetium (177Lu) has no intrinsic pharmacodynamics properties. It is a
medium-energy β-emitter with a maximum energy of 0.5 MeV and a maximum tissue
penetration of 2 mm. The average beta energy is approximately 0.13 MeV. 177Lu also
emits low-energy γ-rays at 208 keV (11%) and 113 keV (6.4%), allowing scintigraphy
and subsequent dosimetry with the same therapeutic compound, if needed. The
177
shorter β-range of Lu compared to other radiotherapeutic agents such as yttrium
provides better irradiation of small tumours, sparing surrounding tissue (the range of
yttrium is 12 mm in tissue, due to the higher energy of 2.27 MeV).
177
Lu decays to stable hafnium (177Hf) with a half-life of 6.647 days. The
177
relatively long half-life of Lu provides logistic advantages that facilitate its supply
177
to locations far from reactors. Endolucin Beta contains Lu, a radioisotope of
Lutetium, as lutetium (177Lu)chloride in solution. It contains 3- 150 GBq Lutetium
(177Lu) chloride which corresponds to 0.73 – 37micrograms of Lutetium (177Lu). The
solution comes in a 2 ml and 10 ml vial where the volume 0.075 -3.75 ml. Lutetium
(177Lu) chloride is produced by the irradiation of highly enriched Ytterbium (176Yb) in
neutron sources with a thermal neutron flux between 1013 and 1016 cm-2 s-1. Non
carrier added (n.c.a.) Lutetium (177Lu) chloride is produced by the irradiation of
highly enriched Ytterbium (176Yb) in neutron sources with a thermal neutron flux
between 1013 and 1016 cm-2 s-1.
The following nuclear reaction is ongoing in the irradiation.
176
Yb(n, γ)177Yb → 177Lu T
The produced Ytterbium (177Yb) with a half-life of 1.9 h decays to Lutetium
(177Lu). In a chromatographic process, the accumulated Lutetium (177Lu) is separated
chemically from the original target material. Lutetium (177Lu) emits both medium-
21
energy beta particles and imageable gamma photons, and has a half-life of 6.647 days.
The primary radiation emissions of Lutetium (177Lu) are shown in table 2-1 taken
from Lutetium (177Lu) principle radiation emission data Radiation(28 April 2016
EMA/CHMP/404078/2016 Committee for Medicinal Products for Human Use
(CHMP) Assessment report EndolucinBeta, european medicine agency ).
Table 2-1 Lutetium (177Lu) principle radiation emission data

Radiation Energy (keV)* Abundance (%)
Beta (β−) 47.66 11.61
Beta (β−) 111.69 9.0
Beta (β−) 149.35 79.4
Gamma 112.9498 6.17
Gamma 208.3662 10.36
2.8.3 Clinical Applications of 177Lu
177Lu include treatment of neuroendocrine tumors (NETs) where cellular receptors

over-expressed on the surface of the cancer cells are targets for the 177Lu-
“DOTATATE” agent, which is an analogue of the hormone somatostatin. The clinical
use of this agent is expanding in several countries. Other key examples of over-
expressed cancer cell target receptors, many of which are being evaluated for
therapeutic targeting with the 177Lu, include bombesin/GRP, CCK/gastrin,
endothelin, extendin, integrin, neurotensin, oxytocin and substance P. Another
therapeutic example is radioimmunotherpay with 177Lu-labeled rituximab®, a
monoclonal antibody useful for treating Non-Hodgkin’s lymphoma. In addition, use
of the 177Lu-“EDTMP” agent is progressing in clinical trials for the reduction of
metastatic bone pain originating from the spread of cancers from the prostate, ovaries
and lungs.(Lutetium-177 radioisotope targeted therapy for treatment of cancer and
other disease, Publication Evolving Important Role of Lutetium-177 for Therapeutic
(Knapp, F. R., & Dash, A. (2016).
22
2.9 QUALITY CONTROL OF 177Lu PRODUCED BY A
REACTOR
177
The therapeutic radionuclide Lu (t1/2=6.73 d), a β- emitter (Eβ-max = 2.28 MeV)
with major γ emissions of 113 keV and 208 keV, is produced by neutron capture reaction
176Lu (n, γ) 177Lu. The target Lu2O3 (176Lu enriched) is irradiated and dissolved
in hydrochloric acid to form a
177
LuCl3 solution. After irradiation, the target is decayed for 3 days for reducing
the activity of
176m
Lu (t1/2=3.66 h) produced by a side reaction [II-14]. The irradiation time
177m
should not too b long to avoid an enhancement of the long-lived isomer Lu
177
(t1/2=160.4 d). Both Lu and
177mLu decays to the
stable 177Hf.
An indirect method to produce 177Lu performs on the radiation of enriched

176
176Yb by the reactions Yb (n, γ) 177Yb, which decays with t1/2=1.91 h to 177
Lu.
The target material Yb is separated from 177Lu by multistep solid phase or
liquid extraction process [II-15]. 177Lu produced via 176Yb path contains no-
carrier-Lu and no 177mLu as an impurity. Several QC tests from 177Lu are shown in
Tabble 2-2..
Table 2-2 Quality Control Tests for 177Lu Prepared via both Pathways
TESTS METHODS SPECIFICATIONS

Appearance Visual inspection Clear colourless solution
pH pH indicator strip 1–2
Identity γ spectrometry, TLCb γ photons of 113 keV and 208
keV
Specific activity ICP-AESa > 2,5 GBq/mg (Lu3+: < 0.4
Metal impurities ICP-AESa Cu: ≤ 1,0
µg/GBq
Fe: ≤0,5
µg/GBq
23
177Lu: > 99.9 %
Radionuclide purity γ spectrometry 177mLu (impurity): ≤ 0.1 %
175Yb
Radiochemical purity TLCb >99 % of 177Lu as Lu3+
Sterility Direct inoculation Sterile
Bacterial Endotoxin LAL test <25 IU/mL
Content
Prepare a 177 Lu solution with 50 MBq/mL and determine the metal ions by
inductively coupled plasma-atomic emission spectrometry (ICP-AES).
177
LuCl3 is analysed by paper chromatography on Varian ITLC SG using saline
adjusted to pH 2.3 with hydrochloric acid as mobile phase. Rf values: 177LuCl3 = 0.4-
0.7; reference: 177Lu-DTPA > 0.9.(IAEA web1856).
2.10 Gallium 68
2.10.1 Radionuclide 68Ga
• ß + (%) 88
• Production route Cyclotron/ Generator
2.10.2 Production
Gallium-68 is a generatoreluted, short-lived radionuclide decaying 89%
through positron emission (maximum energy of 1.92 MeV, mean 0.89 MeV). The
long physical t1/2 of the parent radionuclide (270.8 d) allows the use of the generator
for up to one year, obviating the need for a cyclotron on site, providing cost-
effectiveness as well as convenience.
However, energy of the emitted positron from 68Ga is higher than that of 18F
(maximum energy = 0.63 MeV, mean = 0.25 MeV), the most widely used PET
isotope, which can potentially lead to lower resolution (Sanchez-Crespo et al., 2004).
Gallium-68 is a positron-emitting radioisotope that is produced from a 68Ge/68Ga
24
generator. As such it is conveniently used, decoupling radiopharmacies from the need
for a cyclotron on site.
2.10.3 Clinical applications

Gallium-68-labeled peptides have been recognized as a new class of
radiopharmaceuticals showing fast target localization and blood clearance. 68Ga-
DOTATOC, 8Ga-DOTATATE, 68GaDOTANOC, are the most prominent
radiopharmaceuticals currently in use for imaging and differentiating lesions of
various somatostatin receptor subtypes, overexpressed in many neuroendocrine
tumors (Banerjee, S. R., & Pomper, M. G. (2013). There are now many target-specific
68
Ga-based radiopharmaceuticals undergoing clinical trials (Al-Nahhas et al., 2007;
Breeman et al., 2011a). Peptide receptors with overexpression on a variety of human
tumors are promising biological targets in nuclear oncology. Targeting SSTR has
been particularly vigorously pursued for proof-of-principle for the use of 68Ga-PET
agents in the clinic. Somatostatin is a regulatory peptide, widely distributed in the
human body, the action of which is mediated by membrane-bound SSTR present in
normal human tissues, such as the thyroid, brain, gastrointestinal tract, pancreas,
spleen and kidney (Patel, 1999; Reubi et al., 1997; van der Lely et al., 2003). SSTR
are also abundant in a variety of human tumors, particularly neuroendocrine tumors
(NET) as well as on renal cell carcinoma, small cell lung, breast and prostate cancer,
and malignant lymphoma (Reubi et al., 2001).
68
The contribution of Ga to the promotion and expansion of clinical research
and routine positron emission tomography (PET) for earlier better diagnostics and
68
individualized medicine is considerable. The potential applications of Ga-
comprising imaging agents include targeted, pre-targeted and non-targeted
imaging(68Ga-Based Radiopharmaceuticals: Production and Application
Relationship, Irina Velikyan 1,2, Molecules ,2015 july, ISSN 1420-3049
www.mdpi.com/journal/molecules)
2.11 QUALITY CONTROL OF 68Ga
2.11.1 Quality Control Of 68Ga Obtained from a

68Ge/68Ga Generator
25
68Ga [t1/2=67.7 min, Eβ+max = 1.92 MeV (89%)], a positron emitting
radioisotope is conveniently availability from 68Ge/68Ga generator by decay of the
parent 68Ge (t1/2=270.95 days), as seen in Table II-1. 68Ga labelled somatostatin
receptor-avid peptides (e.g. [68Ga] DOTATOC) are routinely used for PET imaging
of neuroendocrine tumours.
The PET 68Ge/68Ga generator 68Ga-eluate purity / 68Ge breakthrough
I. Develop generators of sufficiently low breakthrough II.
II. Register those generators for human use
III. Define legal definitions for 68Ge levels
To ensure a sufficiently low level of the parent radionuclide germanium-68,
the gallium-68 can either be adsorbed in the form of [GaCl4]− on an anion
exchange column followed by elution from the column in the form of Ga3+
cations with water or diluted HCl, or be adsorbed in the form of trivalent
gallium on a cation exchange column followed by elution with an
acetone/hydrochloric acid mixture
The high positron emission fraction (89%, Emax: 1899 keV, Emean: 890 keV)
and half-life of 68 min provide sufficient levels of radioactivity for high quality
images while minimizing radiation dose to the patient and personnel. It requires short
scanning time and allows repetitive examinations. In modern generators 68Ga is
obtained in ionic form compatible with subsequent highly reproducible and
straightforward labeling chemistry.
The only oxidation state stable at physiological pH is Ga(III) providing robust
labeling chemistry with ligands that can fill the octahedral coordination sphere of
Ga(III) with six coordination sites. The long shelf-life generator (t½ (68Ge) = 270.95
d) is simple to use and a steady source of the radionuclide for medical centers without
cyclotrons or remote from distribution site(68Ga-Based Radiopharmaceuticals:
Production and Application Relationship, Irina Velikyan 1,2, Molecules ,2015 july,
ISSN 1420-3049 www.mdpi.com/journal/molecules).
26
Table 2-3 Quality Control Tests for 68Ga From 68Ge/68Ga Generator Eluted
with Dilute Hydrochloric Acid
TEST METHODS SPECIFICATION OF
S
Appearance Visual examination Clear 68 a
colourless solution
pH pH indicator strip Maximum 2
Radionuclide identity Follow the decay pattern of Half-life 62 to 74 min
68 b of decayed
Analysis Minimum 99.9 % of the total
Radionuclidic purity
sample using radioactivity as
68Ge breakthrough Analysis of decayed <0.001 %
sample using
Radiochemical purity Paper chromatography Minimum 95 % of the total
using 10 mM EDTA as radioactivity due to
Fe: 10 µg/GBq
Chemical purity ICP-AES/ICP-MS f
Zn: 10 µg/GBq
Bacterial Endotoxin LAL test 175 EU/Total volume
Content
68Ga chloride solution for radiolabelling. European Pharmacopoeia Monograph
No.2464:
Identity: Place a small aliquot of [68Ga] GaCl3 (in a test tube) in a well type NaI
(Tl) scintillation counter. Record the counts at fixed intervals of time, setting
appropriate energy window for detecting the 511 keV radiations of 68Ga. Note down
the counts and the time of counting. Plot the decay curve [Time on X axis vs. Counts
(in log scale) on Y axis]. Determine the half- life of the 68Ga sample from the slope
of the decay curve.
Radionuclidic purity: Allow the 68GaCl3 eluted from the generator to decay for 48
hours. Analyse the decayed sample using an HPGe detector coupled to a multi-
channel analyser (MCA) for the presence of emitting impurities.
68Ge breakthrough: As 68Ge decays exclusively by electron capture to 68Ga, the
presence of 68Ge impurity in 68Ga eluate cannot be directly determined by
27
spectroscopy. Allow the 68GaCl3 eluted from the generator to decay for 48 hours.
Analyse the decayed 68Ga sample using an HPGe detector coupled to a MCA.
Measure the 511 keV radiations from the 68Ga daughter, which corresponds to the
68Ge impurity present in the sample
e Radiochemical purity: An aliquot of the 68GaCl3 eluted from the generator be
analysed by paper chromatography on a Whatman™ 3 mm chromatography paper (12 x
1 cm) using 10 mM EDTA as mobile phase. In this system, 68Ga(III) moves towards
the solvent front (Rf = 0.9-1.0) while colloidal and non-cationic 68Ga species remain
close to the origin.
Chemical purity: Presence of trace metallic impurities in the 68GaCl3 solution can
be quantified by ICP-AES analysis of a decayed sample. Calibration curves for the
trace metal ions of interest (eg. Fe, Zn) are obtained using standard solutions
containing known concentration of these trace metal ions.
2.11.2 Regulatory Aspects Of Ge\Ga 68 Generator

Generator is involved in the GMP production process and should comply with the
requirements that would assure: product quality; patient safety; traceability of the
process; reliability and robustness of the performance. Quality assurance system is
necessary to ensure that quality and safety of 68Ga-based radiopharmaceuticals is
adequate for the intended use. The qualification and validation of the performance of
a chromatographic generator includes the investigation of its elution profile, elution
efficiency, the extent of radionuclidic contamination of the eluate, contamination of
the eluate with other metal cations and column material. To be suitable for the use in
nuclear medicine, a generator must have favorable properties when these vital
parameters are examined (Velikyan, I. (2015).
2.11.3 Quality Control Of 68Ga Produced By Cyclotron
68Ga can be produced by small size biomedical cyclotrons by proton irradiation of

68Zn targets [II-1, II-2]. After irradiation, 68Ga is recovered into a concentrated HCl
solution and loaded onto a cation exchange resin [II-3]. After several washing steps,
68Ga is eluted from the column by using dilute hydrochloric acid, and the eluate is
28
directly transferred on a column containing DGA resin. The second column is
rinsed, and 68Ga is eluted with water.
Table 2-4 The List Of The Tests Performed, Methods And Specifications
(Acceptance Criteria) Recommended For Cyclotron Produced 68Ga
Clear and colourless solution
Appearance of the solution Visual examination
Free from visible particulates
pH pH indicator strip Maximum 2
Radionuclidic identity Half-life Half-life between 65 and 71
determination minutes
Radionuclidic purity HPGe γ spectrometry Minimum 99.9 % of the total
radioactivity as
Radiochemical identity tR ± 10% (comparison with
Cation-exchange
Radiochemical purity ≥standard)
95.0%
HPLCa
Fe: ≤ 10
ppm
Chemical purity ICP-MS
Cu: ≤ 10
ppm Ni:
Bacterial endotoxin content LAL test ≤ 175 EU/injection
29
2.12 Quality Control Of 213Bi Obtained From A 225Ac/213Bi Generator
225 229
Ac [t1/2 = 9.9 d] can be produced by radiochemical separation from a Th source or via
cyclotrons by proton irradiation of 226Ra targets (226Ra- (p,2n) 225Ac) [II-17 - II-20] and can be
loaded on a generator [II-21]. 213Bi [t1/2=45.6 min, E = 8.4 MeV and E= 440 keV, 26.1 % emission
probability) is eluted from the column by using a 0.1 mol hydrochloric acid/sodium iodate solution
into solution containing buffer and ascorbic acid. The buffer is depending on the 213Bi chelating
agent. Sodium acetate buffer (4 M) is recommended for CHX-DTPA ((p- SCN-Bz)-
cyclohexyldiethyIenetriaminpentaacaticacid) and TRIS (2-Amino-2-
(hydroxymethyl) propane-1,3-diol, 2M) for DOTA (1,4,7,10 tetraazacyclododecane-1,4,7,10-
tetraacetic acid) chelators.
Table 2-2 demonstrates the recommended quality control tests for 213Bi as prepared at the
European Commission, Joint Research Centre, Directorate G. Nuclear Safety and Security,
Karlsruhe, Germany. Note that sterility and bacterial endotoxin testing is performed as a post-
released control for the final labelled radiopharmaceutical. The ICP-MS analysis is usually
performed randomly in an indirect manner, deduced from previous testing of generators of identical
type.
Table 2-5 Quality Control Tests are recommended for 213Bi
Clear and colourless solution

Appearance of the solution Visual exapansion
Free from visible particles
5.3 to 5.7 for sodium acetate buffer
pH pH indicator strip
8.5 to 9.0 for TRIS buffer
Radionuclidic identity Half-life determination Half-life between 43 to 50 minutes
Minimum 99.9 % of the total radioactivity as
Radionuclidic purity HPGe γ spectrometry 213Bi
Sum of non-radioactive cations
Chemical purity ICP-MS < 1 µg/mL
Bacterial endotoxin content LAL test ≤ 175 EU/injection
2.12.1 Biokinetic studies
For a new radiopharmaceutical, the determination of reference levels of irradiation and

consequently of the risks associated with the administration first requires an accurate determination of
the biokinetics of the tracer. This step is usually carried out via quantitative imaging, blood sampling
30
or excreta measurements in a restricted number of patients (or healthy volunteers). Some data are
also derived from preclinical experiments in animals. Pharmacokinetics modelling is also often used at
this stage. Then, based on the tracer distribution in space and time, radiation dose is calculated using
phantoms, i.e. computational models that mimic organ geometry, organ-to-organ distances, and body
composition of patients (Eberlein, U., et, al., 2011).
Information about following parameters is necessary for dosimetric calculations. Capillary
Blockade , Phagocytosis ,Compartmental Localization ,Active Transport , Chemisorption (also known
as Physicochemical Adsorption) ,Cell Sequestration , Exchange Diffusion ,Simple Diffusion (also
known as Passive Diffusion). Antigen/Antibody Reaction , Receptor Binding , Metabolic Trapping are
also kept into account.
To produce excellent quality images, other factors are important i.e Gamma energy should be
between 100-250 kev and teff should ideally be about 1.5 times duration of test . It is very important
to have a high target to non-target ratio In order for the mechanisms of localization to produce
excellent therapeutic results, other factors are important: In case if the radioisotope should be a pure
beta- or alpha emitters.Energy should be high (> 1 MeV) teff should be moderately long, e.g., days
and Critical to have a high target:non-target ratio.
2.13 Regulatory Aspects of Dose Calculations

The methodology used to assess radiation safety [should] be specified including reference to the body
models that were used
• The mathematical equations used to derive the time activity curves and the radiation absorbed dose
estimates [should] be provided along with a full description of assumptions that were made .
Sample calculations and all pertinent assumptions [should] be listed and submitted
The reference to the body, organ, or tissue model used in the dosimetry calculations [should] be
specified, particularly for new models being tested.
If a software program was used to calculate the radiation doses [one should provide] a full
description of the code, including official name, version number, and computing platform; a literature
citation for the code; and photocopies of the code’s output, preferably showing all of the user input
data and model choices.”
An assessment of any significant radiation hazards to other patients and health care workers should
also be undertaken.
Applicants should provide a description of which organs have a significant accumulation of
activity over time, information on the activity levels at different times (with at least two time points
obtained per phase of radionuclide uptake or clearance), and an evaluation of the time integrals of
31
activity, description of how they were obtained, and a description of how they were combined with
dose conversion factors to obtain doses (if not done by software ).
Approval of a new medical imaging agent includes several phases: A preclinical phase, in
which studies in an appropriate animal species are carefully planned and executed, to provide a
preliminary assessment of the possible radiation doses expected in human subjects. Excerpt from U.S.
Food and Drug Administration. Guidance for Industry Developing Medical Imaging Drug and
Biological Products, Part 1: Conducting Safety Assessments. U.S. FDA, Washington, DC, 2004.
extrapolation of animal data to humans is far from an exact science. Results from such studies
represent an important first step in the evaluation, but they should always be viewed with caution, in
anticipation of more reliable results from the human data obtained in other phases.
Phase 1 studies of medical imaging agents, which are designed to obtain pharmacokinetic and
human safety assessments, based on a single mass administration and escalating mass administrations
of the drug or biological product. The FDA recommends that evaluation of medical imaging agents
that target a specific metabolic process or receptor include assessments of its potential effects on any
relevant processes or receptors.
Phase 2 studies of medical imaging agents include: “refining the agent’s clinically useful mass
dose and radiation dose ranges or dosage regimen (e.g., bolus administration or infusion) in
preparation for phase 3 studies; answering outstanding pharmacokinetic and pharmacodynamic
questions; providing preliminary evidence of efficacy and expanding the safety database; optimizing
the techniques and timing of image acquisition; developing methods and criteria by which images will
be evaluated; evaluating other critical questions about the medical imaging agent.”
Phase 3 studies are designed to confirm the principal hypotheses developed in earlier studies,
demonstrating the efficacy of the compound and method employed, to verify the safety of the use of
the medical imaging agent, and to validate the necessary instructions for use of the compound and for
imaging in the population for which the agent is intended.
The U.S. Food and Drug Administration (FDA) sets standards for the use of lasers (21CFR)
and other non-ionizing radiation, food irradiation, and pharmaceuticals. Medical imaging agents are
submitted for approval in:
Investigational new drug applications (INDs)
New drug applications (NDAs)
Biologics license applications (BLAs)
Abbreviated NDAs (ANDAs)
Supplements to NDAs or BLAs.
Radiation safety assessment associated with the approval of use of medical imaging agents shall
follow these criteria [shall] allow a reasonable calculation of the radiation absorbed dose to the whole
body and to critical organs upon administration to a human subject
32
At a minimum, radiation absorbed dose estimates [shall] be provided for all organs and
tissues in the standardized anthropomorphic phantoms established in the literature • For diagnostic
radiopharmaceuticals [one should calculate] the effective dose as defined by the International
Commission on Radiological Protection (ICRP) in its ICRP Publication 60
The amount of the radiation absorbed dose delivered by internal administration of diagnostic
radiopharmaceuticals be calculated by standardized methods [should be provided.
33
3 LITERATURE REVIEW
In order to develop effective radiopharmaceuticals for therapy, it is essential to carefully

consider the choice of appropriate radionuclides as well as the carrier moiety with suitable
pharmacokinetic properties that could result in good in vivo localization and desired excretion
(Volkert et al., 1991; Wessels and Rogus, 1984; Fritzberg et al., 1995). The major criteria for the
choice of a radionuclide for radiotherapy are suitable decay characteristics, ease of production and
amenable chemistry. As regards the decay characteristics, physical half-life of the radionuclide should
match with the biological half-life of the radiopharmaceutical. The energy of the particulate emission
should be compatible to the volume of lesion to be irradiated and at the same time should result in
minimal dose delivery to the tissues surrounding the site of localization. Also, the ratio of non-
penetrating to penetrating radiation should be high (Volkert and Hoffman, 1999; Srivastava and
Dadachova, 2001; Qaim, 2001; Ehrhardt et al., 1998; Mausner et al., 1998).
Other practical considerations in selecting a radionuclide for targeted therapy are availability in
high radionuclidic purity as well as high specific activity and production logistics. The major criteria
for choice of a radionuclide for therapeutic use include the radionuclidic half-life, the type, energy,
and branching ratio of particulate radiation, as well as photon abundance and energies. It is important
to match the physical half-life of the radionuclide with the biological half-life of the carrier molecule
used. Other important considerations include the availability of convenient and high-yield chemical
strategies for stable attachment of the radionuclide to the carrier molecule, specific activity (activity/
mass), radionuclidic and chemical purity, production feasibility, and cost. There are a large number of
radionuclides which show potential use for the development of therapeutic radiopharmaceuticals.
While it is difficult to select any one radionuclide as ideal or the best suited for therapy, a few will
have more desirable properties than others for a desired application. (Banerjee, S., Pillai, M. R. A., &
Knapp, F. F. (2015).
Radiopharmaceuticals are required to meet the criteria of purity, identity, efficacy and safety, as for
radiopharmaceuticals, and to comply with the precautions associated with the safe handling of
radioactive materials (Westera and Johannsen, 1997, pp. BP5).
A basic regulatory strategy, which ensures the safety of public health, relies on product development,
roduct manufacture, and Post Marketing Surveillance studies of the product (Tobin and Walsh, 2008)
During product development, manufacturers are required to generate sufficient data, which proves the
safety and efficacy of the product. Should the RA deem this data as acceptable, a Marketing
34
Authorization Furthermore, radiopharmaceuticals are required to be administered by specially trained
physicians (SNMMI, 2004), who have been trained in the administration and control of
radiopharmaceuticals, as opposed to the generalized training received by physicians in the
administration of intravenous pharmaceuticals.
In the selection of starting materials the main aspects that should be considered for orthodox
pharmaceuticals, is the effect of the materials on the stability and impurity profile of the product (as
well as on the establishment of the product specifications), generally with the view of toxicity profiles
to the patient. However, the ICH Q3 guidelines exclude radiopharmaceuticals, and do not consider
the sensitivity of many radiopharmaceuticals to even trace amounts of impurities. Many
radiopharmaceutical API products are required to be of an ultra-pure specification in order to ensure
the adequate control and manipulation of the FPP for patient administration. One aspect which has
not been taken in to account, is the fact that the ultra-pure starting materials are supplied by a limited
number of suppliers only, making their control and release (e.g. QC testing on receipt, as well as
qualification of the supplier) a challenge, albeit critical, due to the lack of equipment and analyst
capabilities. In addition, the potential to contaminate these with impurities introduced by analytical
grade reagents used during the QC process, also poses a concern. Therefore, extra controls in the
form of supplier qualifications, method validations, standardized procedures and stringent training
programs may be required.
Licensed radiopharmaceuticals are to be used following the instructions and recommendations

of the manufacturer. All other radiopharmaceuticals have to be analysed before use according to a
monograph of the European Pharmacopoeia or another pharmacopoeia. If the radiopharmaceutical is
not described in a pharmacopoeia, methods of analysis have to be developed and validated and should
comprise for injectable preparations: appearance of solution, identity of radionuclide and of
radiolabelled compound, radiochemical purity, level of chemical impurities, residual solvents, specific
activity, pH, bacterial endotoxins, sterility, radionuclidic purity. Tests on bacterial endotoxins, sterility
and radionuclidic purity may be performed after product utilisation for tracer agents labelled with a
short-lived radionuclide provided the process has been duly validated. Reference to a general
monograph on radiopharmaceutical preparations published by an official pharmacopoeia may
represent a useful guidance
Toxicological information with respect to radiopharmaceuticals used in early phase clinical trials
If in vitro data on metabolism and comparative data on primary pharmacodynamics and biological
activity are available, the toxicity study can be limited to: – an extended single-dose toxicity study in
only one (appropriate) mammalian species including a control group and both genders of animals.
35
The number of animals must be sufficient to ensure reliable interpretation of the study results.
‘Appropriate mammalian species’ is specified as ‘if the choice of species could be justified based on
comparative in vitro metabolism data and by comparative data on in vitro primary
pharmacodynamics/biological activity’. – the study period is 14 days with interim killing of a number
of animals at day 2 (day of dosing=day 1); – allometric scaling from animal species to man with a
safety factor of 1,000 with non-radioactive analogue (but possibly solubility problems for lipophilic
tracers); – information to be collected on haematology and clinical chemistry (day 2+day 14) and on
histopathology after killing the animal. Information must also be collected on any organs where the
test substance localises and organ systems intended to be visualised by the test compound; – gross
necroscopy should be performed on all animals.
Genotoxicity studies In vitro genotoxicity studies should be performed as recommended in the
relevant ICH guidance. However, if the test substance belongs to a well-known chemical class for
which genotoxicity data are available on other class representatives, performance of reduced versions
of mutation test in bacteria (Ames test) and chromosome aberration, mouse lymphoma or in vitro
micronucleus tests may be sufficient. On the other hand, the EMEA “Guideline on the limits of
genotoxic impurities” [14] does not require genotoxicity testing in case the amount of test substance to
be administered does not exceed 1.5 µg for a single administration or 1.5 µg/day for
Dosimetry information with respect to radiopharmaceuticals used in early phase clinical trials
Justification of activities that could cause or affect radiation exposures, – Optimisation of protection to
keep doses as low as reasonably achievable,
Use of dose limits (dose constraints).
Justification of activities that could cause or affect radiation exposures(guidelines )
Licence for operation of the radioactivity instalations
Below are recommendations for radiation- and ligand-related safety assessment.
Evaluation of radiation-induced toxicity: A general toxicology study with the radiopharmaceutical
usually is not warranted. The animal biodistribution and dosimetry studies, together with the general
knowledge of organ-specific radiation-induced toxicities, are usually sufficient to address toxicities
from the radiation. Published articles on organ-specific radiation-induced toxicities should be
included in the submission. Sponsors should consider the addition of safety endpoints, such as
clinical signs, body weight (BW), hematology, and serum chemistry, into the design of the
biodistribution study.
Evaluation of ligand-induced toxicity: To identify any ligand-related toxicities, sponsors should
conduct a general toxicology study with the cold pharmaceutical in a relevant species before initiation
of a FIH study. Ligand-related toxicities have been observed but are usually minor compared with
radiation-induced toxicities, and hence, a study in one species is generally considered sufficient.
Unless otherwise justified, the species selected for toxicology study should be the same as the species
36
used for animal biodistribution and dosimetry study. Frequency of administration in the toxicology
study should follow recommendations in the ICH guidance for industry Nonclinical Evaluation for
Anticancer Pharmaceuticals and should take into account the frequency of administration in the FIH
trial (both the human biodistribution and dosimetry and the therapeutic phase that follows it).
Long-Term Toxicity Assessments to Support Marketing In general, the nonclinical data and the
clinical phase 1 data should be sufficient for moving to phase 2. Sponsors should conduct long-term
toxicity assessment studies to support marketing, and the results should be submitted with the
marketing application. These studies should assess both ligand- and radiation-related toxicities. The
dosing period in animals can follow ICH S9. For most pharmaceuticals intended for the treatment of
patients with advanced cancer, nonclinical studies of 3 months’ duration are considered sufficient to
support marketing. Below are recommendations for study design and circumstances when studies may
not be needed. Contains Nonbinding Recommendations Draft — Not for Implementation .Evaluation
of ligand-induced toxicity: Chronic toxicity studies of the cold pharmaceutical may not be needed in
several circumstances: when a limited number of doses are administered to patients (e.g., two or three
doses), when the ligand is for delivery purposes only and administration will result in a small dose
(e.g., in microgram ranges), or when the cold pharmaceutical has a short half-life and dosing
frequency is low (e.g., every 4 to 8 weeks). When a chronic study is needed, a study in a single
species is generally considered sufficient. This study can be combined with the late radiation toxicity
study. Evaluation of late radiation toxicity: An assessment of late radiation toxicities is warranted
when patients have a long life expectancy that could be affected by late radiation adverse effects. For
recommendations on animal study design and endpoints, see the guidance for industry Nonclinical
Evaluation of Late Radiation Toxicity of Therapeutic Radiopharmaceuticals. Identification of a no
observed adverse effect level is not needed. The study in a single species is generally considered
sufficient. When a limited number of organs is examined by histopathology, the organs selected
should be justified. Any organs with gross pathology finding should be examined microscopically. B.
Genotoxicity, Reproductive Toxicology, and Carcinogenicity Studies No genetic or reproductive
toxicity or carcinogenicity study with the radiopharmaceutical or the cold pharmaceutical is
warranted during drug development or for approval. Alpha, beta, and gamma radiation cause
deoxyribonucleic acid damage and are inherently genotoxic and carcinogenic, and damage male and
female germ cells and a developing conceptus. These risks should be communicated in product
labeling (see section VII., Labeling Recommendations().
Radiopharmacy, practice particularly in the PET field, has to adjust to an ever increasing regulatory
framework both in Europe and the US. This involves all aspects of RP preparation, from clinical trial
applications, GMP-practices, facility design, professional requirements and quality aspects.
Regulatory authorities need to be aware of the unique characteristics of PET RPs, including the short
half-life and need for single-dose patient preparations, to allow incorporation of rapid scientific
37
advances in the field. Activities of professional organizations may assist in finding appropriate
solutions for this highly specialized field, but it remains with the regulators to support these efforts to
allow the true potential of PET to develop for use in molecular imaging and drugs(Radiopharmacy:
regulations and legislations in relation to human applications Clemens Decristoforo1, Sally W.
Schwarz Department of Nuclear Medicine, Innsbruck Medical University, Innsbruck, Austria 2
Department of Radiology, Division of)
The regulatory procedures necessary to control radiopharmaceutical products are in large part
determined by the sources of these products and the methods of manufacture. Manufacturing
procedures within the scope of these guidelines
Radiopharmaceuticals can be classified into four categories:
1. Ready-for-use radioactive products.
2. Radionuclide generators.
3. Non-radioactive components (“kits”) for the preparation of labelled compounds with a radioactive
component (usually the eluate from a radionuclide generator).
4. Precursors used for radiolabelling other substances before administration (e.g. samples from
patients).
the name of the product and a description of its use; (b) the contents of the kit; (c) the identification
and quality requirements concerning the radiolabelling materials that can be used to prepare the
radiopharmaceutical, namely: — the directions for preparing the radiopharmaceutical, including the
range of activity and the volume, together with a statement of the storage requirements for the
prepared radiopharmaceutical; — a statement of the shelf-life of the prepared radiopharmaceutical; —
the indications and contraindications (pregnancy, children, drug reactions, etc.) in respect of the
prepared radiopharmaceutical; — warnings and precautions in respect of the components and the
prepared radiopharmaceutical, including radiation safety aspects; — where applicable, the
pharmacology and toxicology of the prepared radiopharmaceutical, including the route of elimination
and the effective half-life; — the radiation dose that a patient will receive from the prepared
radiopharmaceutical; — the precautions to be taken by users and patients during the preparation and
administration of the product and the special precautions for the disposal of the container and any
unconsumed portions; — a statement of the recommended use of the prepared radiopharmaceutical
and the recommended dosage; — a statement of the route of administration of the prepared
radiopharmaceutical; — if appropriate for particular kits (i.e. those subject to variability beyond the
recommended limits), the methods and specifications needed to check radiochemical purity.
Production and distribution records
1 The processing records of regular production batches must provide a complete account of the
manufacturing history of each batch of a radiopharmaceutical, showing that it has been manufactured,
tested, dispensed into containers and distributed in accordance with the written procedures.
38
2 Separate records for the receipt, storage, use and disposal of radioactive materials should be
maintained in accordance with radiation protection regulations.
3 Distribution records should be kept. Since the return of radioactive products is not practical, the
purpose of recall procedures for such products is to prevent their use rather than an actual return. If
necessary, the return of radioactive products should be carried out in accordance with international
and national transport regulations.
8. Quality assurance and quality control
Radiopharmaceuticals are nearly always used before all quality control testing (e.g. tests for sterility,
endotoxin, radionuclidic purity, etc.) has been completed. The implementation of and compliance with
the quality assurance programme are therefore essential.
8.2 Quality assurance and/or quality control should have the following principal responsibilities:
(a) the preparation of detailed instructions for each test and analysis;
(b) ensuring the adequate identification and segregation of test samples to avoid mix-ups and cross-
contamination;
(c) ensuring that environmental monitoring and equipment and process validation are conducted as
appropriate for evaluating the adequacy of the manufacturing conditions; (d) the release or rejection of
starting materials and intermediate products;
(e) the release or rejection of packaging and labelling materials;
(f) the release or rejection of each batch of finished preparation;
(g) the evaluation of the adequacy of the conditions under which the starting materials, intermediate
products and finished radiopharmaceutical preparations are stored;
(h) the evaluation of the quality and stability of the finished products and, when necessary, of the
starting materials and intermediate products;
(i) the establishment of expiry dates on the basis of the validity period related to specified storage
conditions;
(j) the establishment and revision of the control procedures and specifications;
(k) assuming the responsibility for retaining samples of radiopharmaceutical products;
(l) assuming the responsibility for keeping adequate records of the distribution of the
radiopharmaceutical products. Whenever the size of the establishment permits, quality assurance and
quality control duties should be organized in separate groups. Quality assurance should also include
the monitoring and validation of the production process.
A manufacturer’s quality control laboratory should be separated from the production area.
The control laboratory should be designed, equipped and of such a size as to be a self-contained
entity, with adequate provision for the storage of documents and samples, the preparation of records
and the performance of the necessary tests.
39
The performance of all qualitative and quantitative tests mentioned in the specifications for the
starting materials may be replaced by a system of certificates issued by the supplier of these materials,
provided that:
(a) there is a history of reliable production;
(b) the producer or supplier is regularly audited;
(c) at least one specific identity test is conducted by the manufacturer of the finished
radiopharmaceutical.
Samples of the intermediate and final products should be retained in sufficient amounts and under
appropriate storage conditions to allow repeated testing or verification of a batch control. These
samples should be kept for an appropriate period in accordance with the shelf-lives of the radioactive
components concerned. However, this may sometimes not be applicable, e.g. for radiopharmaceuticals
with a short half-life.
Sampling procedures may be adapted to the purpose of the sampling, the type of controls being
applied, and the nature of the mate- vial being sampled (e.g. a small batch size and/or its radioactive
content). (World Health Organization WHO Technical Report Series, No. 908, 2003 Annex 3
Guidelines on Good Manufacturing Practices for radiopharmaceutical products)
by the sources of these products and the methods of manufacture
Because of their short half-lives, many radiopharmaceuticals are released and administered to patients
shortly after their production, so that quality control may sometimes be retrospective. Strict adherence
to GMP is therefore mandatory.
The specification for the amount of radioactivity and radiochemical history of reliable production;
impurities may deviate from general principles of assay and related substances due to limitations of
the measurement procedures, the special chemistry involved and the small chemical amounts present.
Reference Standards or Materials (3.2.S.5) Information on calibration standards used in radioactivity
measurements should be provided.
If an appropriate traceable standard of the isotope is not available, justification for the use of another
method of calibration should be included
The shelf life and the storage conditions for the active substance should be specified and justified.
The general stability guidelines are fully applicable to the non-labelled active substance applied in
radiopharmaceutical kits and chemical precursors for the production of PET radiopharmaceuticals.
starting materials may be replaced by a system of certificates issued by the supplier of these materials,
40
starting materials may be replaced by a system of certificates issued by the supplier of these materials
41
4 MATERIALS AND METHODS
4.1 FDG18
The 2-[18F]fluoro-2-deoxy-D-glucose injection, an analogue of glucose (also referred to as
FDG, [18F]FDG, fludeoxyglucose or fluorodeoxyglucose), is a positron emitting radiopharmaceutical
containing no-carrier added radioactive. 18F, and is used in conjunction with Positron Emission
Tomography for diagnostic medical imaging.
FDG production is a multi-step process that begins with a particle accelerator (typically a
small or medium energy cyclotron) which produces the [18F]fluoride radionuclide through proton
irradiation of oxygen-18 enriched water (target material) in a small enclosed volume (typically, 0.5–
2.5 mL). After sufficient irradiation time (usually not more than three hours), the radioactive
[18F]fluoride is transferred to a radiopharmaceutical production laboratory for further transformation
into FDG suitable for injection.
The [18F]fluoride is collected inside an FDG synthesizer in a hot cell. Several automated
chemical manipulations are carried out within the synthesizer, leading to a product which is ultimately
formulated into a physiological injection solution and subjected to either sterilizing filtration or steam
sterilization. The final product, FDG, can then be collected directly into a sterile injection vial or
further fractionated (dispensed) into several different vials or syringes. The synthesizer and the
dispenser (if used) are placed inside lead shielded hot cells to provide protection to operators from the
ionizing radiation emanating from the product. The hot cells are also designed to provide an
environment of air classification compatible for pharmaceutical manufacturing. The entire FDG
manufacturing process may be confined to the clean room environment or within controlled zones to
help ensure the pharmaceutical quality of the finished product. A clean environment is
particularly important for FDG manufacturing when the product is not subjected to terminal
sterilization. Attention to aseptic manufacturing, therefore, is an essential component of FDG
manufacturing.
The final step in the FDG manufacturing process is the assessment of quality and assurance of
conformity to required quality specifications. Therefore, before a product is released for patient use, a
series of quality control tests are to be performed on a representative test sample. The required quality
parameters are assessed with validated test methods and equipment. Records are generated and the
required documentation is evaluated for correctness prior to product release.
The frequency of FDG production depends entirely upon the scope of a producing facility and the
number of PET centres being served by a facility. It may be synthesized only once or twice during a
24 hour period in a small production facility, followed by packaging and delivery to PET sites. On the
other hand, production may be performed multiple times a day in a busy facility. FDG is provided to
PET centres as a ready to use solution with all the necessary quality attributes of an injectable product.
42
The solution may be packaged in single dose or multiple dose glass vials and generally does not
contain any preservatives
4.2 Synthesis of FDG:

Synthesis of FDG begins with the production of [18F]fluoride in a cyclotron, typically in a
target chamber containing [18O]H2O, followed by a nucleophilic reaction with 1,3,4,6-tetra-O-acetyl-
2-O-trifluoromethanesulfonyl-β-D- mannopyranose (mannose triflate), and subsequent de-blocking of
the protecting groups (acetyl), resulting in FDG formation Synthesis is generally
performed in an automated synthesis module placed in a hot cell with a controlled air environment.
Several synthesis modules are commercially available, and all are practically based on the method
reported by Hamacher et al. (Hamacher et al. (1986). The production yield is reasonably good,
typically >65% (corrected to EOB) within 25–45 minutes after collection of [18F]fluoride.
The precursor molecule for the radiochemical synthesis of FDG is 1,3,4,6-tetra-O-
acetyl-2-O-trifluoromethanesulfonyl-b-D-mannopyranose (see Fig. 5.2(1)), commonly called mannose
triflate. This is a sugar molecule containing a suitable leaving group (trifluoromethanesulfonyl, also
called triflate) for a facile nucleophilic reaction at carbon 2 in the molecule, while the other four
potential reaction sites are blocked with protecting groups (tetra-acetyl).
4.2.1 Step 1: Irradiation of 18O water with protons
18
The O(p,n)18F reaction with 18
O enriched water produces 18
F. Typical irradiation
parameters include:
— 18O enrichment, typically >95%;
— Chemical purity of 18O enriched water, higher than 99.99%;
— Target volume, ranging from 0.5 to 2.5 mL;
— Proton beam of 8–19 MeV;
— Beam currents of 20–100 µA;
— Irradiation time from 30 min to 3 h.
The total amount of [18F] fluoride which can be produced. Other factors influencing total
yield will be 18O enrichment in water, chemical purity of enriched water, target material, target volume
and target design. As discussed in Section 4, one can expect approximately 111 GBq (3 Ci) of
[18F]fluoride in a single target during one hour of irradiation with a 10–13 MeV proton beam at a
beam current of 50 µA, and approximately 167 GBq (4.5 Ci) for a higher energy machine
(14–19 MeV). The yield can be enhanced by increasing beam current and irradiation time as
well as by using dual targets.
43
The chemical purity of enriched water is critical for longer irradiations with high beam
currents. The benefit of longer irradiation needs to be carefully optimized, as the yield reaches a
saturation point with long irradiations. Also, heat generated within a target limits the beam current that
may be put onto a target. Nevertheless, with a customary useful FDG yield of >65% (EOS yields
corrected for decay), several curies of FDG can be produced in a single irradiation/production cycle
for in-house use, as well as for distribution to other PET centres.
13
The oxygen-16 present in the target water leads to the production of N through an (n,α)
reaction, which is a radionuclidic impurity. Nitrogen-13 is a radionuclide decaying through positron
13
emission with a half-life of 10 minutes and hence a major part of the N will decay during the
synthesis of FDG, leaving trace amounts. Nitrogen-13 can appear in several chemical forms including
nitrate, nitrite, nitrogen and ammonia, depending on target conditions. Also, depending on the method
of synthesis and purification of FDG, some amount of 13N may be present in the final product, which
will result in a shorter measured half-life.
4.2.2 Step 2: Extraction of [18F] fluoride the H2O18

After irradiation of enriched water, the mixture 18F/[18O]H2O is transferred from the target onto
a pre-conditioned anion exchange separation cartridge such as a QMA (quaternary ammonium anion
exchange) SepPakTM column. The 18F ions are retained on the cartridge, while unused [18O]H2O and
cationic and other impurities are removed from the target and collected in a waste vial. Trapped 18F is
subsequently eluted from the cartridge with a solution containing K2CO3 and the phase transfer
catalyst (Kryptofix 2.2.2) in acetonitrile and pharmaceutical grade water. The [18F]KF/Krytofix
complex eluted is collected in the reaction vial. Quantities of K2CO3 and Kryptofix 2.2.2 vary
depending upon the synthesis module. Typically, >95% of 18F activity is retrieved. It is to be noted
that chloro- deoxyglucose (ClDG), a potential chemical impurity in FDG, may form if an anion
exchange resin is used in chloride form and is not conditioned properly.
This potential impurity can be controlled in FDG by displacing chloride ions from the
resins. The unused 18O enriched water can be recovered from the waste vial for further use. However,
it is important that impurities are removed through an efficient purification process prior to reuse for
production of [18F]fluoride. The recovered [18O]H2O water from different batches can be pooled
together and purified. However, the quality of the purified enriched water must be verified prior to its
use for production of [18F]fluoride. Purification (not to be misconstrued as enrichment) is required to
remove the dissolved organics (acetonitrile, acetone and ethanol) arising from various sources,
particularly with non-cartridge synthesis modules. The cost of the enriched water may be a
determining factor in a decision to reuse it. GMP protocols in some Member States may not allow the
reuse of 18O enriched water.(
44
4.2.3 Step 3: Drying of [18F]fluoride
Effective drying of fluoride (virtual freedom from water) is a critical factor for a nucleophilic
reaction to occur efficiently, leading to an eventually high yield of FDG. The required dryness is
achieved through repeated azeotropic evaporation with anhydrous acetonitrile at ~85° C under inert
gas and/or vacuum. It is essential that during each solvent removal step, the mixture be completely
dry, and also that vessel temperature does not exceed 100ºC in order to prevent the decomposition of
Kryptofix 2.2.2.
Nucleophilic displacement reactions with fluoride are known to be quite difficult and
unpredictable because of the fluoride ion being a weak nucleophile in an aqueous media, leading to
very poor yields. In a polar aprotic media such as acetonitrile, fluoride undergoes nucleophilic
reactions rather quickly. However, for fluoride to become an effective nucleophile, it must be
18
available as reactive fluoride. The F/K2CO3/Kryptofix 2.2.2 complex is effectively an organic
cation/inorganic anion salt soluble in acetonitrile, making the [18F]fluoride
available in a highly reactive form.
4.2.4 Step 4: Labelling of the mannose triflate with the 18F
In the synthesis of [18F]FDG based upon the method of Hamacher et al. [5.1], the 1,3,4,6-tetra-O-
acetyl-2-O-trifluoromethanesulfonyl-beta-D-mannopyranose (mannose triflate) precursor reacts with
[18F]fluoride through nucleophilic displacement. Although various precursor substrates have been
described in literature, the use of triflate as the leaving group in the nucleophilic reaction with
[18F]fluoride is found to be the most efficient, rapid and clean option. The reaction between the dry
18
mixture of F/K2CO3/Kryptofix prepared in the previous step and mannose triflate in anhydrous
acetonitrile at ~85° C provides a high yield of intermediate labelled 18F in less than 5 minutes. An
added advantage of using acetylated mannose triflate is that after the nucleophilic displacement of the
triflate group by 18F, the acetyl groups can easily be removed by hydrolysis (acid or base) to yield
FDG.
4.2.5 Step 5: Removal of the protective acetyl groups by hydrolysis to

form FDG
The final chemical step in FDG synthesis is removal of the four acetyl protecting groups,
which is easily accomplished through hydrolysis with either a mild acid or a base. Both methods are
equally effective. Alkaline hydrolysis is the most commonly used method in commercial synthesis
modules, since it requires less time and a lower temperature. In this case, the 18F-labelled intermediate
with intact acetyl groups is treated with a mild base (1–2 M NaOH) at room temperature to remove
45
the acetyl groups. Alkaline hydrolysis may be performed directly on a C-18 cartridge at room
temperature instead of adding base to the reaction vessel (Schlyer et al. (2009)
One possible drawback is that alkaline hydrolysis has the potential for epimerization of FDG
to [18F]Fluorodeoxymannose (FDM), which is a radiochemical impurity that should be controlled in
the FDG manufacturing process. It has been shown, however, that the formation of FDM is a
possibility only if hydrolysis is performed at a higher temperature (Meyer et al. (1999). epimerization
at room temperature is negligible with an NaOH concentration of ≤ 2M.
4.2.6 Step 6: Purification and formulation of the final FDG product
FDG is purified by passing through a series of columns (such as SepPakTM cartridges) for
removal of impurities. These columns could include (not necessarily in this order):
— Cation exchange for removal of Kryptofix 2.2.2 or TBA;

— Alumina for removal of unreacted [18F]fluoride;
— Ion retardation for neutralization and pH adjustment;
— C-18 or similar lipophilic column for removal of unhydrolysed and partially hydrolysed lipophilic
intermediates.
In some synthesis modules, the unhydrolysed intermediates are trapped on a C-18 column and
impurities are washed out prior to hydrolysis. The final step of formulation process includes adjustment
of isotonicity, pH and volume. Some synthesis units utilize cation exchange and ion retardation resins
to neutralize a solution, while others use buffers and the addition of a calculated quantity of
hypertonic NaCl or Na2CO3 or NaH2PO4 to achieve the pH and volume required for the final product.
For formulations consisting of high activity, the addition of a stabilizer may be considered. It would
then be essential to determine the safe and effective use of a stabilizer, as well as supplying a
quantitative assessment of stabilizer amount in the final preparation.
4.2.7 Step 7: Sterilizing filtration
Sterilizing filtration is performed by passing purified FDG solution through a 0.22 µm filter.
Sterilization with steam (autoclave) may be applied in addition to sterilizing filtration, but is not seen
as mandatory. The application of steam sterilization has the advantage of relatively reducing
environmental control during synthesis and dispensing. In the case of sterilization filtration, it is
46
essential that its effectiveness is accompanied by the assurance of a low bioburden upstream,
production under aseptic conditions and the testing of filters used for integrity prior to parametric
release of the final product.
4.2.8 Step 8: Sampling for quality control and quality assessment
To sample for quality control and quality assessment, a representative test sample is removed
from a well-mixed bulk solution. Sampling must be done aseptically to ensure no contamination of the
final product. The sample size is usually about 0.5 mL for QC, and about 1.0 mL is retained in case
repeat tests are needed or there are product complaints. A retention sample may not be necessary; this
is determined by the applicable national regulation. Tests for required quality attributes are performed
using a test sample and the results are compiled prior to release of FDG radiopharmaceutical for
patient use.
4.2.9 Step 9: Dispensing
The qualified FDG may be delivered to a PET centre as a multi-dose vial without further
manipulation, or it may be dispensed into unit doses using either manual or automated systems. This
process must be done in an aseptic manner and in a controlled environment, as required by the
applicable GMP regulation. The product vial (or syringe) and outer lead shielding should be affixed
with labels containing product information, including product name, total activity at reference time,
expiration time and other pertinent information. Samples of such labels are found in Section A–8 of
the Annex to this book.
4.2.10 Step 10: Packaging and shipping
Two primary concerns during packaging and shipping are: radiation protection of workers and
the general public, and the maintenance of product integrity. Compliance with the applicable
regulations and guidelines for radiation protection and transportation of dangerous goods must be
observed during packaging and shipping (for example, International Air Transport Association (IATA)
regulations). FDG is shipped either in a multi-dose vial or as unit doses in a vial or in syringes. A lead
container — together with some absorbent material to take care of inadvertent spillage — is packed in
a secondary container. Appropriate labels must be affixed on the vials/syringes, the lead containers
and on the final packages before shipping.
47
4.3 Quality Control of F18-FDG
Quality control plays an important role in the production and supply of 18F-FDG as it is a legal
obligation to ensure that the product is physiologically absolutely safe prior to distribution (Weiler,
2000). Below is a list of Quality control tests which should be conducted prior to distribution of 18F-
FDG, with the exception of the bacterial endotoxin test. Visual Inspection The F18-FDG dose must be
colourless, clear and free of particles and should be inspected behind sufficient shielding(Hung, 2002).
Radionuclidic Identity and Radionuclidic Purity To evaluate radionuclidic identity, a sample of
the 18F-FDG is placed in a dose calibrator to be measured. Once measured, both the time and the
activity should be noted. After 20-30 minutes, the sample should be remeasured and time and activity
should be noted once again. The half-life can then be calculated using the equation, t1/12= -In2(time
difference/[(end activity/starting activity)]) and must be within the range of 105-115 minutes(Yu,
2006).
Chemical Purity Chemical purity testing is performed on any chemical substance that is either
used or formed en route during the 18F-FDG synthesis process(Yu, 2006). The determination of the
glucose content is achieved by High Performance Liquid Chromatography (HPLC). During the
synthesis process, not only 18F-FDG, but also glucose and depending upon which method of synthesis
used, 2-chloro-2-Deoxy-D-glucose (2-CIDG) in the case of acid hydrolysis and 2-18F-FDM in the case
of alkaline hydrolysis are formed. Therefore, it is very important to carry out chemical purity testing
due to the analytic separation of those very similar compounds(Weiler, 2000).
The use of a strong basic anion exchange column with a mobile phase of 0.1M NaOH and the
flow rate of 1ml/min should be used to carry out HPLC(Weiler, 2000). HPLC is performed by
injecting and run the HPLC of a reference standard solution and then run the HPLC of the test
solution. The results should show that the area under the FDG peak should be less than that of the
reference solution, to be within acceptable limits(Yu, 2006).
It is also necessary to test for any residue of the phase transfer catalyst. This is performed by
thin layer chromatography (TLC) and in the case of 18F-FDG, it is used for the detection of potential
residues of Kryptofix, the aminopolyether. 2µl of the product solution is applied to a plate next to a
spot of reference solution containing the phase transfer catalyst in a concentrated limit of 2.2mg per
dose. The plate is then developed using a mixture of 1 volume of ammonia and 9 volumes of
methanol(Weiler, 2000). It is then dried for 15 mins and the plate then exposed to iodine vapour,
making the aminopolyether spots visible. A visual comparison is then made between the intensity of
the spots to assess the aminopolyether concentration of the product. The test solution spot should have
a colour lighter than the reference solution spot(Yu, 2006).
48
4.3.1 Radiochemical Purity and Radiochemical Identity
To evaluate radiochemical purity, High Performance Liquid Chromatography (HPLC) and
Thin Layer Chromatography (TLC) methods can be used. In the case of the HPLC method, a suitable
activity detector should be used and the calculated peak areas should correspond to the percent of the
total activity. 18-FDG and 18F-FDM combined must represent 95% of the activity. The 18F-FDM
share of the total percentage should be at most, 1/10th(Weiler, 2000). Radiochemical Identity is
determined by Thin Layer Chromatography (TLC). TLC is conducted using a silica plate, called the
stationary phase and with an eluent consisting of 95% acetonitrile and 5% water, called the mobile
phase and a TLC scanner. The Rf of the 18F-FDG, free 18F, and acetylated 18F-FDG are 0.45, 0.0
and 0.8 to 0.95. The spotting technique has quite a significant effect on TLC results, therefore the spot
size should consistently be between 2 to 5 µL(Hung, 2002).
4.3.2 Filter Integrity test

Due to that fact that 18F-FDG is released and injected into patients prior to the release of
sterility testing, there is no direct way to assure the sterility of the product. The filter integrity test is
an indirect way to determine if the product is sterile. The theory behind this is that if the integrity of
the filter is not compromised, the filter would have performed its function and therefore removed any
bacteria present in the 18F-FDG product(Yu, 2006).
There are a few filter integrity testing devices available on the market, although the
mechanism behind them are the same. A stream of air is passed through the device to reach the filter
and then to a reservoir of water. An indicator will then show the pressure put upon the filter
membrane by the air stream. The filter membrane should be able to withstand the maximum pressure
indicated in the specification of the filter. If the membrane is broken, stream will pass through the
filter membrane and into the water reservoir, causing air bubbles to appear(Yu, 2006).
4.3.3 Residual Solvent

Gas Chromatography (GC) is a method used to measure the presence of residual solvents such
as; dehydrated alcohol, ether and acetonitrile in 18F-FDG. The GC test should be performed using
flame ionisation detection. Residual solvents can remain in the final preparation of the 18F-FDG dose
and may have potential toxic, pharmacologic and physiologic effects to the patient. Therefore,
residual solvent testing must be carried out to ensure that any residual solvent with the potential to be
toxic must be within appropriate limits. The acceptable limits are as follows; 0.04% acetonitrile, 0.5%
dehydrated alcohol and 0.5% ether present in the final 18F-FDG product(Hung, 2002).
How does gas chromatography work?
The eluent is introduced from a gas cylinder called a gas carrier sits external to the machine and
essentially carries the test sample through the machine. The carrier gas is also called the mobile phase.
49
The flow rate of the carrier is carefully controlled to allow for the best separation of the components
in the sample.
The carrier gas then enters the machine through an inlet port. The test sample is then injected
into the carrier gas and via a syringe and is vaporized. The vaporised test sample separate out as it
moves along a column, this is called the stationary phase. The column is comprised of a very thin,
long tube which is contained within an oven like structure inside the machine. To ensure that the gas
test sample remains in gas form, the oven is kept at a high temperature. The gas separates and travels
along the column at different speeds. A detector senses and records them. The detector used in the
case of 18F-FDG, is the flame ionisation detector. The data is collected and recorded and the machine
creates a chart with peaks representing the relative amounts of different chemicals(Woodford, 2009).
4.3.4 Stabiliser Test

A stabiliser may be added to the formation of 18F-FDG. A stabiliser is added to reduce radio
lytic degradation of 18F-FDG with a high specific concentration. If there is a potential for the added
stabiliser to have a toxic, physiological or pharmacological effect on a patient, it must be evaluated to
ensure it meets the acceptance limits (Hung, 2002).
4.3.5 PH
PH levels of an injectable radioactive tracer should be as close to physiological pH as possible.
PH level testing can be performed with the use of pH test paper. It is recommended that narrow-
banded test paper is preferable, for example, a colour change for each 0.5 pH unit. Traceability and
accuracy of the pH paper should be verified with a standard pH buffer. The acceptable pH range
for 18F-FDG is between 4.5 and 8.5 and this test must be completed before the product is released
(Hung, 2002).
4.3.6 Sterility testing

Sterility refers the presence of any bacteria and microorganisms which may have originated at
the time of radiopharmaceutical preparation. Post release sterility testing must be completed for every
individual batch of 18F-FDG. The 18F-FDG must be inoculated on both fluid thioglycolate medium
(FTM) and soybean casein digest medium (SCDM) within 30hrs of production at 37 degrees. The
FTM is a media for anaerobic bacteria and SCDM for aerobic bacteria. The sterility test takes up to 14
days to complete and therefore does not allow for prerelease results(Yu, 2006). Since the
radiopharmaceutical is released and used clinically before the results are available, the final 18F-FDG
product is passed through a 0.22µm filter(Hung, 2002). Laboratories should allow a 24-hour period of
decay to avoid harmful radiation exposure(Yu, 2006).
50
4.3.7 Bacterial Endotoxin test
The limulus amebocyte lysate (LAL) test is used to assess the presence of bacterial endotoxin
in radiopharmaceutical preparation. A bacterial endotoxin is a component of the cell wall of Gram
negative bacteria(Keech, 2012). The gel-clot assay method is used and is based on the formation of
the gel clot in the presence of endotoxin(Yu, 2006). This method uses a lysate of amoebocytes from
horseshoecrab, Limulus Polyphemus(Weiler, 2000). The presence of the endotoxin should not exceed
175/V per millilitre of 18F-FDG, V being the maximum administered total dose, in millilitres, at the
expiration time(Hung, 2002). The test kit requires an incubation period of 20- 60 minutes(Yu, 2006).
4.4 FDG18 quality control specifications according to European

PHARMACOPIEA
The Ph.Int., Ph. Eur. and USP define these limits in relation to the maximum injected volume V to a
patient. For clarification in this table, values were calculated assuming a maximum volume (V) of 10 mL
and specifications presented here as maximum concentration/mL. perform all the required tests. Some
tests are meant to be performed on undiluted samples, while others may require dilution, which must
be done quantitatively to ensure accurate results. The proposed sampling station should be set up
behind appropriate lead shielding to protect the operator from radiations.
4-1 FDG18 quality control specifications according to European Pharmacopoiea
QUALITY SPECIFICATION
PARAMETER METHODS
Appearance Colourless or slightly yellow solution
Visual inspection
The radionuclidic and radiochemical A. Gamma
identity are combined in the spectrum, using a
following fashion:Either tests A and gamma
Identity C, or B and C spectrometer
(radiochemical may be applied. B. Dose calibrator
and A. Gamma ray spectrum exhibits a or gamma counter
radionuclidic) major peak of 511keV; TLC with
B. The half-life is between105–115 radioactivity
minutes; scanner
C. Distribution of radioactivityon a
TLC strip corresponds to FDG
Radionuclidic Not less than 99% of total Gamma

purity radioactivity is due to 18F spectrometer
Not less than 95% of total TLC with

Radiochemical radioactivity in the test radioactivity
51
purity chromatogram corresponds to FDG. scanner
±10% of stated activity Dose calibrator
Assay of
radioactivity
pH pH value, 4.5–8.5 pH paper (validated
with pH meter
Chemical purity Not more than 0.22 mg/mL TLC
Kryptofix 2.2.2
Chemical purity: Not more than 0.275 mg/Ml HPLC

tetraalkylammon Only to be measured if employed in
ium ions synthesis.
Chemical purity: Not more than 0.05 mg/Ml HPLC

2-Chloro-2-
deoxy-D-glucose
Chemical purity: Not more than 1 mg/mL HPLC

2-Fluoro-2-
deoxy-D-
Glucose
Residual No more than 0.04% acetonitrile and GC with FID

solvents: 0.5% ethanol detector
acetonitrile and (Based upon USP and Ph. Eur.
ethanol specifications); this quality parameter
is not mentioned in Ph.Int
Bacterial Not more than 17.5/mL LAL (Limulus
endotoxins amoebocyte lysate
Sterility Must be sterile Microbial growth in

culture media
Chapter 5
5 RESULTS AND DISCUSSIONS
5.1 Evaluation of quality control and dosimetric Facilities at INMOL

HOSPITAL WITH RESPECT TO IAEA and European Pharmacopoiea
Standard Specifications
52
Quality control parameters were compared with standard specifications of Eu pharmacopoeia
mentioned , and were evaluated on the basis of checklist criteria. Points were assigned on the basis of
fulfilling the meeting criteria for standard specifications.
Table 5-1 18FDG parameters evaluation
18FDG
Biokinetic studies 9
Radiotoxicity Studies 8
Clinical trials studies 9
Patient dosimetry 7
Drug handeling and patient preparation techniques 7
Medical staff compliance 9
Equipment compatibility 8
Equipment quality control compliance 8
Workload 9
Economical effectiveness and cost benefit analysis 9
Storage,handeling and radiation protection preparedness 8
5.1.1 FDG 18
10
9
8
7
6
5
4
3
2
1
0
Figure 5-1 FDG18
53
5.1.2 GALLIUM 68
Table 5-2 Gallium 68 parameters evaluation

68Gallium
18FDG parameters evaluation Radiotoxicity Studies 7
Patient dosimetry 6
Workload 7
54
9
8
7
6
5
4
3
2
1
0
Figure 5-2 Gallium 68 parameters evaluation
5.1.3 LUTITIUM 177 Parameters evaluation
Table 5-3: Lutitium 177 parameters evaluation
177Lutitium
Radiotoxicity Studies 6
Patient dosimetry 5
Workload 4
55
9
8
7
6
5
4
3
2
1
0
Figure 5-3: Lutitium 177 parameters evaluation
5.1.4 Comparison of quality control and dosimetry facilities for 18

FDG, and Gallium 68,Lutitium 177 at INMOL Hospital with respect to
IAEA standard specifications
Table 5-4 evaluation of radiopharmaceuticals with comparative specifications and acceptance

criteria of parameters
equipment equipment quality medical staff cost effective radiation
compatibility control compliance analysis protection
FDG18 9 9 9 9 8.5
Gallium 8 8 8 6 8
68
Lutitium 7 7.5 7 3 7
177
56
10
9
8
7
6
5
4
3
2 FDG18
1 Gallium 68
0
Lutitium 177
Figure 5-4 : Comparison of quality control and dosimetry facilities for 18 FDG, AND
GALLIUM 68,LUTITIUM 177, at INMOL HOSPITAL
Table 5-5 evaluation of radiopharmaceuticals with comparative specifications and acceptance

biokinetic clinical trials radiotoxicity patient drug handeling

studies studies studies dosimetry technology
FDG18 9 9 8.5 8 8.5
Gallium 8 7 7.5 6 7
68
Lutitium 7 7 6 5 6
177
57
10
9
8
7
6
5
4
3
2 FDG18
1
0 Gallium 68
Lutitium 177
Figure 5-5 evaluation of radiopharmaceuticals with comparative specifications and acceptance

5.2 Discussions
It is essential that several key parameters be controlled during manufacturing in order to
maintain consistent and reliable production which results in a product conforming to required quality
characteristics., FDG conform to required quality specifications before it can be released for
patient use.
5.2.1 Good manufacturing practice

FDG is an injectable radiopharmaceutical, and hence must be manufactured in a manner
compatible with the GMP regulations applicable for each production facility. the information is readily
available in various GMP guidelines on radiopharmaceuticals manufacturing (IAEA web1515)
Due to the short half-life of 18F, all the mandatory quality control tests needed for releasing an
injectable product cannot be finished prior to the release of FDG (parametric release). Therefore,
control of materials and supplies and careful handling, in particular handling of synthesizer
assemblies in an aseptic manner, should result in a product conforming to all the required
attributes of quality and safety.(IAEA web 1515)
Nucleophilic substitution reaction is the only method used in the production of FDG. Furthermore, the
production of FDG has been considerably simplified by the use of automated synthesis modules that
are designed for operation under a controlled environment facilitating GMP compliance.
It is to be noted that although a recommendation can be made regarding the value of
conducting a particular test prior to releasing a product batch, the responsibility to ensure compliance
with applicable regulations remains with the producer. Regulations regarding the manufacture of PET
radiopharmaceuticals are evolving and hence there is no harmonized manner in which FDG must be
produced. Clearly then, not all GMP guidelines for FDG manufacturing are the same. On the one
58
hand, the need for compliance is not much different from the GMP( Elsinga et al& Radiopharmacy
Committee of the EANM. (2010).
Guidelines for manufacturing conventional pharmaceuticals (EU and WHO). On the other
hand, there are GMP guidelines that are specifically tailored for manufacturing PET
radiopharmaceuticals (US FDA). Regardless of the regulation in force, it must be understood by all
concerned parties that the ultimate aim of an FDG manufacturing facility is to integrate
applicable processes such that each product batch meets quality requirements.
It must be emphasized that due to the relatively large quantity of radioactivity being handled
18
and the short half-life of F, several restrictions are imposed that must be overcome during
manufacturing. Furthermore, as the product is generally not subjected to steam sterilization and is
approved for use through parametric release, it is essential that appropriate controls are applied during
manufacturing.
Finally, proper planning and management in relation to the most critical components of GMP
listed below should lead to a product that consistently and reliably conforms to the required quality
attributees: 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.
59
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)
5.2.2 Regulatory aspects of PET radiopharmaceuticals in the USA and

EUROPE
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 radio-
pharmaceuticals 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 special-
ists 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
60
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 recommenda-
tions 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.
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 vari- ously
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 elabo- rated 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 radio-
pharmaceuticals, 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.
5.2.3 Quality aspects of PET radiopharmaceuticals

Even costly implementation and maintenance of quality system for a PET radiopharma-
ceutical 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
61
and efficacy for patient care and a reliable quantitative performance in both diagnostic
diagnos 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 guide
lines 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 5-6 inter connection of QA ,GMP,Production and QC

The inter-relationship for whole quality system in PET radiopharmaceutical manufacturing.
manufacturing
Particularly, QC procedure of PET radiopharmaceutical is usually critical and essential, since
it is synthesized every day or is small-scale
small “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:
1. Appearance, by visual assessment;
2. pH determination;
3. Radionuclidic identification, by gamma-ray spectrometry or half-life measurement;
4. Radionuclidic purity, by gamma-ray
gamma spectrometry;
5. Chemical purity, by high-pressure
pressure liquid chromatography (HPLC) or by thin-layer
thin chro-
matography (TLC);
62
6. Radiochemical purity, by HPLC with a radioactivity detector or by TLC with a radioactivity
scanner;
7. Rasidual solvants by gas chromatography
8. Bacterial endotoxins, by a rabbit test or limulus amebocyte lysate (LAL) test;
9. Radioactivity, by a validated dose calibrator and.
10. Sterility, by incubating the sample with fluid thioglycollate medium (FTM) at 30~35°C
for 14 days or with soybean casein digest (SCD) medium at 20~25°C for 14 days.
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).
1. 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.
5.3 Guidelines
1. The facility design in hospital should incorporate product protection considerations,
including a controlled environment;
2. Staff should have appropriate qualifications, experience, job specific training and a
good quality culture’.
3. A quality assurance programme with appropriate authorizations should be in place;
4. Materials management (procurement, quality verification, storage and use) should be
considered;
5. Documentation and records (standard operating procedures, batch records)must be properly
maintained;Aseptic processing and monitoring are necessary.
63
6. Appropriate equipment (production and quality control) must be used;
7. Risk assessment and validation of processes should be undertaken
8. QA department of hospital must assure that Radiopharmaceuticals are designed and prepared
according to the latest state of knowledge.
9. Preparation and control operations are clearly specified and implemented according to the
principles of cGRPP.
10. Radiopharmaceuticals are only supplied for use in patients if they have been correctly
processed, checked and stored in accordance with the defined procedures and released by a
competent person.
1. The performance of all qualitative and quantitative tests mentioned in the specifications for
the starting materials may be replaced by a system of certificates issued by the supplier of
these materials
2. Adequate measures are in place to ensure that radiopharmaceuticals are released, stored and
handled in such a way that the required quality can be assured throughout their shelf-life and
in accordance with the in-use expiry date.
3. The aseptic work area should be suitable for the preparation of a sterile SSRP.
4. Air quality in the aseptic processing area should be adequately controlled to limit the presence
of microorganisms and particulate matter.
5. There must be appropriate procedures for the sanitization of materials and equipment being
transferred into the aseptic work area. Critical activities in the preparation and testing of a
SSRP should be conducted in an aseptic workstation with a grade A rating (e.g. a LAFW or
isolator). Critical activities are steps in the procedures that expose the SSRP or surfaces of the
container/closures that will be in contact with the product to the environment. Examples of
such activities include
64
(1) the aseptic assembly of sterile components (syringe, needle, filter and vial) for sterile
filtration of the SSRP,
(2) open vial dispensing,
(3) sampling of the sterility test samples, and
(4) sterility testing of the finished radiopharmaceuticals
6. Equipment used in the preparation, QC and dispensing of SSRPs must be appropriate for its
intended function and not contaminate the product. All equipment may potentially affect the
quality and purity of a SSRP, or give erroneous or invalid test results when improperly used
or maintained.For this reason, it is of paramount importance that the equipment is suitable for
its intended purposes, properly installed, maintained and capable of repeatedly producing
valid results.
7. all equipment used to perform the testing should be suitable for their intended purposes and
capable of producing valid results.
8. Gas chromatograph At the beginning of each day of use, the analyst should make sure that the
GC system is functioning correctly by at least one injection of a standard preparation
(reference standard or internal standard) before the injection of test samples, and the retention
time must be within predefined limits.
9. HPLC system the actual purification chromatogram must be carefully compared with
previous results. The HPLC system must have detectors suitable for the intended purpose and
be of sufficient sensitivity. At the beginning of each day of use, the analyst should make sure
that the HPLC system is functioning correctly by analysing a suitable reference standard. At
least one injection of a standard preparation (reference standard or internal standard) should
be done before the injection of test samples and the retention time must be within predefined
limits.
10. Radionuclide activity calibrator the accuracy and linearity of a radionuclide activity calibrator
used to measure the radioactivity of SSRPs should be assessed at installation and at
appropriate intervals there after. The instrument should be calibrated in accordance with
nationally recognized standards or the manufacturer’s instructions.
11. A system suitability test should include the measurement of a reference radionuclide standard
source of suitable emission energy. For some radionuclides it is crucial to determine geometry
correction factors on installation of a radionuclide activity calibrator.
12. Radiochromatogram scanner It is recommended that a radiochromatogram scanner (or
equivalent equipment that provides a radiochromatogram) is used for measuring radioactivity
distribution on thin-layer chromatography plates. The scanner should have sufficient
sensitivity and spatial resolution for the intended discriminatory and quantitative objectives.
Checks and maintenance recommended by the manufacturer should be performed.
65
13. Multichannel analyser A multichannel gamma spectrometer coupled to a calibrated sodium
iodide scintillation detector, or preferably the higher resolution lithium compensated
germanium [Ge(Li)] detector, is typically used to determine radionuclidic purity and to
identify any contaminant radionuclides. The overall system should have sufficient sensitivity
and resolution for the intended purpose. Adequate calibration and preventive maintenance
should be performed in accordance with the manufacturer’s specifications. More frequent
intervals should be used if problems in the operation of the multichannel analyzer are
encountered.
14. Automated synthesizer and automated injectors should be used to avoid unnecessary
exposures.
15. reagents, solvents, the radiopharmaceutical itself or, in general, with any components
involved in the preparation and dispensing of the SSRP, are not reactive, additive, or
absorptive, so as to ensure that the quality of the finished product is not altered.
16. Each laboratory should have and follow written procedures to ensure that equipment is
routinely calibrated, inspected, checked and maintained, and these activities should be
documented
17. Most analyses use reference standards. It is recommended that small-scale radiopharmacies
establish the reference standards identified in the analytical procedure or SOP or described in
the pharmacopoeia. If a hospital radiopharmacy establishes its own reference standards, it is
recommended that data to fully confirm the material’s identity and purity be established and
documented. Documentation such as reference spectra or other supporting data to prove the
identity and purity of the reference standard may be available from the supplier.
18. Vendor selection It is recommended only qualified vendors be used to control starting
material. A vendor is qualified when there is evidence to support its ability to supply a
material that consistently meets all quality specifications. Vendor qualification can be done
on the basis of a visit (audit), on the basis of responses to a QA questionnaire, or simply on
the basis of experience with this supplier. In any case, the vendor qualification should be
documented. It is also recommend that small scale radiopharmacies ask the vendor to report
any major changes in the manufacture of an item.
19. It is preferable to have more than one qualified vendor for a component. A vendor should be
replaced if there is an indication that it is supplying unsatisfactory materials.
20. The specification for the amount of radioactivity and radiochemical history of reliable
production; impurities may deviate from general principles of assay and related substances
due to limitations of the measurement procedures, the special chemistry involved and the
small chemical amounts present. Reference Standards or Materials (3.2.S.5)
21. Information on calibration standards used in radioactivity measurements should be provided.
66
22. If an appropriate traceable standard of the isotope is not available, justification for the use of
another method of calibration should be included.
23. The shelf life and the storage conditions for the active substance should be specified and
justified.
24. The general stability guidelines are fully applicable to the non-labelled active substance
applied in radiopharmaceutical kits and chemical precursors for the production of PET
radiopharmaceuticals.
25. The performance of all qualitative and quantitative tests mentioned in the
specifications for the starting materials may be replaced by a system of
certificates issued by the supplier of these materials.
26. Dosimetry information with respect to radiopharmaceuticals used in early phase clinical trials
should be kept into account.
27. Justification of activities that could cause or affect radiation exposures, Optimisation of
protection to keep doses as low as reasonably achievable,
28. Use of dose limits (dose constraints) must be ensured.
29. Activities that could cause or affect radiation exposures(guidelines ) should be justified.
30. At a minimum, radiation absorbed dose estimates should be provided for all organs and
tissues in the standardized anthropomorphic phantoms established in the literature
31. For diagnostic radiopharmaceuticals [one should calculate] the effective dose as defined by
the International Commission on Radiological Protection (ICRP) in its ICRP Publication 60
32. The amount of the radiation absorbed dose delivered by internal administration of diagnostic
radiopharmaceuticals be calculated by standardized methods should be provided.
33. Licence for operation of the radioactivity installation must be acquire.
67
Chapter 6
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Zimmer, A. M., Director, N. P., & Officer, R. S. (2004). Radiation Protection and Radiation
Measurement Issues with Non-Traditional Radiopharmaceuticals.
72
Appendix
A-1
Checklist for Evaluation of New Radiopharmaceuticals

for Clinical Use
6 Radioisotope Properties
What is the Radioisotope present in radiopharmaceutical or

intended to buy?
What is the Purpose of Radiopharmaceutical? (
imaging/therapy , or theranostics)
What are the modes of decay(alpha, beta or gamma) of the
radioisotope?
What is the Principal Radiation Emission Data of radioisotope?
(Gamma energy, gamma abundance,)
What is the Half-life of Radioisotope?
What are the physical (liquid or solid) as well as Chemical

Characteristics (molecular forms etc.) of radioisotope?
What are the isomeric transitions of radioisotope?
What are the Biological, Physical, and Effective Half-Lives of

Radioisotope?
Does It possess a half-life which is suitable for diagnostic use?

What is the expected radioactivity
73
What is the radioactive concentration of radioisotope in
radiopharmaceutical?
What are the tagging efficiency with pharmaceutical
What are the radionuclides(initial unstable radionuclide and the

nuclide after transformation),?
What is the radionuclidic purity (%) of radiopharmaceutical?
What is the specific radioactivity of Radioisotope?
What is the total radioactivity of Radioisotope ?
What is Verification of Macroaggregate Particle Size and

Number available for radiopharmaceutical?,
what are the Radioisotope production routes ,pathways

(reactor,generator,cyclotron)?
radionuclide production studies are available in case if YES NO
radioisotope is a reactor based product?
What are the Decay scheme of Radiopharmaceuticals and
daughter products?
If anyone of these results in either any one of these toxic

elements like Cadmium, lead, Nikel, chromium, cupper,
sulpher ,mercury , antimony, bismuth as an ending product
then their possible effects ?
What is the Chemical form of radioisotope?
What is the Radiochemical Purity of Radioisotope?
What are thermal Properties of radiopharmaceutical?
74
What are the Target Transport Systems mechanisms of
Solvent Extraction test are performed for chemical

purifications?,
What are the QC tests for the radiopharmaceutical
What are the methods of Radiochemical Processing and

Purification testing of Radiopharmaceutical?
What are the radioactive contaminants , Non-radioactive

contaminants, Type of Impurity ( radionuclide, radiochemical ,
chemical), their possible Effects?
Radiopharmaceutical is encapsulated? Encapsulated materials?
Radiopharmaceutical is chemically stable during use at room YES NO

temperature?
What are the interactions of Radiopharmaceutical with tissues?
Radiopharmaceutical contain desired identity?
What is the strength, quality, and purity of Radioisotope?
Who is the Radioisotope producer?(manufacturer)?
Who is the Pharmaceutical, Radiopharmaceutical producer?
Name the Country of producer?
Is producer authorized/regulated by his authority? YES NO
6.1 LABELLING EFFICIENCY

In vitro radiolabelling, In vivo radiolabelling, Blood Labelling YES NO
75
studies are available?
what is the extent of RBC survival?
What is the extent of Cell viability in case intravenous?
What is Radiolabelling efficiency of WBCs and platelets of
individuals ?
What is the Labelling efficiency of Radiopharmaceutical ?
6.2 Biokinetics and biodistribution studies for

Radiopharmaceutical
Biokinetic studies of radiopharmaceutical are available? If yes YES NO

then indicate any document/proof of study?
Pharmacodynamics studies are available for this YES NO
Radiopharmaceutical?
What are the Clearance and uptake times of
Plasma clearance is being kept into account? YES NO
What are the Organ/tissue uptake and retention ?
What is the Organ clearance time and redistribution time of

What are the Excretion routes of radiopharmaceutical?
What is the uptake duration of radiopharmaceutical ?
What is the Biological half-life of radiopharmaceutical?
What is the Pharmacokinetics of radiopharmaceutical?
What are the Common mechanisms of localization of

76
What is the First transit of radiopharmaceutical
Simple exchange diffusion mechanism is possible for YES NO

Radiopharmaceutical prone to Active transport? YES NO
Radiopharmaceutical prone to Capillary blockage? YES NO
What are the Compartment localization mechanism ?
Radiopharmaceutical prone to Electrostatic binding with YES NO

cellular atoms and molecules?
Radiopharmaceutical prone to Phagocytosis ? YES NO
What is the Antibody and antibody fragment localization

mechanism for Radiopharmaceutical?
What is the Receptor localization for Radiopharmaceutical?
What are the Cellular sequestration of Radiopharmaceutical?
How Radiopharmaceutical effects the Metabolism?
What are the Excretion routes of radiopharmaceutical?
How Residence Time of Radiopharmaceutical is calculated?
6.3 RADIOTOXICITY STUDIES

Study of radiotoxicity is available for given YES NO
What is the Justification of the study ? provide any document

or proof?
77
Radioactive contaminants are present in Radiopharmaceutical? YES NO
If yes then what are the radiocontminants and their

concentrations?
What is the %Dose due to radiocontaminants?
What is the nature of TOXICITY (Genotoxicity, reproductive

toxicity,Carcinogenesis, Mutagenesis?
Radiopharmaceutical prone to Impairment of Fertility? YES NO
what are their biological and chemical reactions with organs of

body and what is the nature of effects i.e life threatening, death
causing, stochiastic,chronic or acute.
What is the Justification of the study ? provide any document

or proof?
6.4 Drug Handling AND Patient Preparation
What are the Drug Handling techniques for

What is the Dose administration route ?
What are the Target organs?
What is the injected dose of Radiopharmaceutical?
What is the Estimated patient dose per procedure ?
Patient identification? Infection control? YES NO

Patient is assessed (including pregnancy/breast feeding)? YES NO
Patient is Satisfied? YES NO
Mention if any Time Inconvenience to the patient ?
78
Patient is called for repeated clinical exams? YES NO
Volume of Clinical Procedures?
Radiopharmaceutical Referring Physician is Satisfied? YES NO
What is the experience of reffering physician related to

Radiopharmaceutical study and use ,prescribtion?
Name of physician: Qualification of physician:

What is the Experience of relevant study, compensations
Reliability and durabity of treatment ?
What are the Clinical indication(s) including type of exam?
What are the Reasons for limited exams ?
What is the radiotracer dose and type of stress for patient?
What is an overview of the results of the exam including

pertinent positive and negative findings,( include localization
and quantification of abnormal findings),( including stress,
ECG findings ) etc?
What are the Medical emergencies preparedness measures?
1. In case of Vomiting of radio-pharmaceutical by the

patient
2. In case of Death of a patient with administered radio-
pharmaceuticals in the body)
How many Planned Number of Injections for a Patient?
What is the estimated cost per injection?
What is the Frequency of Use of injections?
79
What are the dose preparation time and Administration times?
What is the Reconstituted Vial Volume of Radiolabeled? YES NO
The necessary volume to administer based on calibration time

and dose is being Calculated?
What is the Recommended Dose for Adults?
What is the Recommended Dose for Pediatric Patients?
What are Medical emergencies handling prepapardness

measures?
7 Patient Dosimetry
The studies of radiopharmaceutical on age/weigh- based YES NO

estimated absorbed radiation doses (mGy/MBq) from
intravenous injection/by oral usage are available?
Planned Number of Injections for a Patient,
Frequency of Use,
What are the adverse reactions of radiopharmaceutical?
What are the Hypersensitivity Reactions of

What are the Patient discharge instructions ( if any)?
7.1 Work load
What is the Scanning time per patient for this

What is the Post injection patient waiting time?
80
What is Expected patients load in hospital for given scan?
What are the working hours of hospital and medical facility?
8 Clinical trial studies
What are the Clinical procedure protocols for

radiopharmaceutical studies?
What are target and normal tissues and their dose levels?
What are the estimations of radiation dose to target and normal

tissues on indivisual basis ?
Is there any study available in this perspective? YES NO

Clinical Pathology is kept into account for these clinical YES NO
studies?
What is the Volume of Clinical Procedures?
Clinical trials documentations data for new YES NO

radiopharmaceutical from countries of all over the world is
available?
If yes then provide list of countries those are participating in

these studies?
Authenticated radiopharmaceutical manufacturer data is YES NO

available ?
If yes then provide list of manufacturers and their authorizing

bodies:
Authenticated hospitals of the world in which clinical trials YES NO

are being conducted by researchers are available for these
studies?
81
If yes then provide list of hospitals?
List of Authenticated institutes, medical colleges, universities

from countries of all over the world those are involved in
conducting these studies?
For every clinical procedure: Imaging Therapy YES NO
Exercise/pharmacologic stress Equipment, QA data ,Physician
reporting Outcome and quality assessment Radiation and
laboratory safety Administrative and personnel policies
General Protocol Guidelines,therapeutic index assessment.
Gamma camera and other equipment qc records and any
phantom studies available in clinical studies ?
If yes then provide documented proof of these type of studies?
What are the missing parameters in studies?
Radiation safety Administrative was involved to cope with YES NO

radiation risks in these clinical studies? Any record available?
Results of pre-clinical study are available? Provide if any? YES NO
Pre-clinical study reports are availabe ? provide if any? YES NO
Who is the Procedure approving authority?
Clinical study reports are available ? provide if any? YES NO
What is the Efficacy of novel radiopharmaceutical?
What are the Conventional radiopharmaceuticals for same
study? if any ( mention) ?
Radiopharmaceutical is Compatible according to therapeutic YES NO
and diagnostic needs
(Diagnostic nuclear medicine: high quality images of activity

in the patient, with low patient radiation dose ,
Therapeutic nuclear medicine: high amount of energy imparted
to the target tissue (to destroy cancer cells) relative to critical
normal organs and tissues to prevent radiation damage and side
effects).
what is the Therapeutic index of new radiopharmaceutical in
82
comparison with other radiopharmaceuticals which are under
clinical practice?
What is the Pharmacopoeialmonograph of
Name of physician: Qualification of physician:
What is the Experience of relevant study, compensations
Reliability and durabity of treatment ?
What are the Optimization methods are being adopted related
to radiopharmaceutical prescribtions?
How the Risk/benefit analysis is performed for given

radiopharmaceuticals?
9 Equipment and Instrumentation Compatibility and

Quality Control
Certificates of compliance are available for :
Gamma Camera YES NO
Dose calibrator YES NO
Dose rate meters YES NO
Survey meter YES NO
Contamination monitors YES NO
Personnel dosimetry YES NO
Equipment and instrumentation used in the nuclear medicine YES NO

facility is in good working condition?
uptake probes, survey meters and glucometers be in YES NO
accordance with the PNRA requirements?
A policy exists and be followed for routine inspection and YES NO

testing of all non-imaging equipment such as dose calibrators,
83
The dose calibrator must be calibrated in accordance with YES NO
nationally recognized standards or the manufacturers
instructions?
Dose calibrator or decay correction calculation system, YES NO

as appropriate for the site?
validate energy calibration is performed for Thyroid Uptake YES NO

and Counting Systems?
Thyroid Uptake and Counting Systems – according to each day YES NO
of use to verify energy calibration and sensitivity are
sufficient?
High-Count Floods For Uniformity Correction for SPECT YES NO
Systems (frequency as recommended by a medical physicist)
are sufficient?
Resuscitation (cardiac)equipment and supplies are appropriate YES NO

to the types of procedures being performed?
Exercise equipment (as applicable) is available? YES NO

ECG equipment (as applicable) is available? YES NO
Ancillary monitoring equipment (as applicable)? YES NO
Infusion pumps/automated injectors (as applicable)? YES NO
Temperature recording device are sufficient? YES NO

Gas chromatographs are sufficient for chemical purification YES NO
testing?
High performance liquid chromatograph (HPLC) are available YES NO
and sufficient?
84
The physical facilities and equipment meet requirements for YES NO
compounding, sterile preparations?
buffer area , segregated compounding area, primary YES NO
engineering control systems, HEPA air filtration, including
testing and certification routinely inspected for safety are
properly functioning?
Reagents, solvents, gases, purification columns, and other YES NO
auxiliary materials are Commercially available?
ready-to-use sterile, pyrogen-free, sealed container/closure YES NO

systems for injections, syringes are sufficient?
What are the Inherent components of errors in
radiopharmaceutical’s mislabelling?
appropriate internal control procedures are strictly followed to YES NO

prevent mislabeling of radiopharmaceuticals?
YES NO
transfer sets, and filters used in aseptic process are sufficient?
Is the quality of the images acceptable? YES NO
What are the Medical device design,purchase, manufacturing

and maintainance costs?
Their Availability is sufficient?
How many kits for radiopharmaceutical preparation?
List insufficient equipment for quality control tests?

What is the Detail of QC facilities?
list quality control tests required
Imaging equipment in hospital is compatible with YES NO
85
Survey meter and dose monitors are compatible? YES NO
What is the Sensitivity and Range of survey meters for gamma
rays?
Radiation monitoring devices including: Portable survey meter YES NO
Removable contamination counting equipment (as applicable)
for Fixed area are sufficient?
What is the Sensitivity and Range of contamination monitors

for beta rays?
survey meter and contaminant monitors for dose YES NO
Preparation/storage areas (as applicable) are sufficient?
Dose calibrators are compatible? YES NO
Is there any modification required? YES NO
If yes then what modifications are required?
9.1 Medical Staff Competence
What is the Ability and competence of staff to perform

clinical procedures?
What are the Personnel Qualifications of staff?
What is the Training/inservice for technologists, physicians? ,
In hospital training is appropriate to the tasks performed by the YES NO
individual?
Technical procedure manual are available?
Staff members with clinical expertise are available to assist YES NO

with clinical questions in hospital, formulary reviews?
or other informational requirements needed?
Ensure that personnel are properly trained and qualified, as YES NO
appropriate to use and handle medical equipments)?
86
9.2 Economical and Commercial Analysis of Radiopharmaceutical
New radiopharmaceutical is cost effective ? YES NO

radiopharmaceutical is Manufactured locally? YES NO
Radiopharmaceutical is Inexpensive and readily available? YES NO
What is the Activity to be ordered ?
How long is the radioisotope supply/use contract?
What are the terms and conditions of the contract (document)
What is the Form of delivery of radiopharmaceutical

( Generator/vial)?
If imported then rout of delivery or shipment? By air? Through
sea shipment? Or by road?
What is the Expected time of shipment?
What is the cost of Maintainance facilities & involved
equipments?
Maintainance facilities & involved equipment is sufficient YES NO

according to requirements?
Any modified equipment is required?

Suppliers are documented with contract and guarantee related YES NO
to radiopharmaceuticals production and supplies?
IF YES then for how many years?
What is the Complexity of quantitative procedures?
What is the Cost per injection?

What is the Estimated cost per patient?
87
9.3 STORAGE, HANDLING and Radiation
Protection
Radioisotope is volatile/nonvolatile ?
What are the Storage facilities for radiopharmaceuticals
What are the Injection techniques?
What are the Badging instruments?
What are Current practicing facilities for storage?
Is there any modification is required? YES NO
Mention reasons for modification?

What are Radiation and laboratory safety measures?
Area surveys and Wipe tests for Sealed source inventory are
conducted?
Emergency handling? What are Accidental or emergency
exposure preparedness for radiopharmaceuticals?
What are the emergency procedures to handle and contain
spilled materials safely, including related decontamination
procedures and surveys?
What are emergency procedures for spills posted in the

department?
What are the radioactive spills Adverse effects, Radiation
Risks?
Additional radiation protection measures are required (

Mention if any)?
88
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Evaluation of Implementation of Standard Requirements on

Clinical Use of New Radiopharmaceutical

Department of Physics & Applied Mathematics

― Jalal ud-Din Rumi

Department of Physics & Applied Mathematics

A Thesis Submitted to the Faculty of Applied Sciences of Pakistan Institute of

Head of DPAM: ____________

Figure 1-0-1 dosimetry of therapeutic and diagnostic radiopharmaceuticals ............. 14

their use. Besides, radiopharmaceuticals containing radionuclides of short physical

Radiopharmaceuticals are radiolabelled compounds designed to deliver

1.1.1 Mechanism of action

1.2 Clinical uses of Radiopharmaceuticals

1.3.1 Internal dosimetry is helpful to

1.3.2 Dosimetric systems

1.4 Quality control of Radiopharmaceuticals

Radiopharmaceuticals are the preferred agents for the assessment of function,

1.5 Dosimetry of radiopharmaceuticals

1.6 Dosimetry Quantities and Units

1.7 Medical Internal Radiation Dose System

1.8.1 Usefulness of the Dosimetry Systems

1.9 Models and Resources for Internal Dose

1.10 Input Data for Dose Calculations

1.10.1 Extrapolation of Animal Data

1.10.2 Biological endpoints

On the other hand, very recent research has profoundly challenged

Radionuclide Type of Isotopic half- Example use

2.2 Radionuclide 15O

2.4 Production and Demand of Radioisotopes

2.5 Locally produced

2.7 Intended to Buy

2.8 LUTITIUM 177

2.8.2 Decay Characteristics

Table 2-1 Lutetium (177Lu) principle radiation emission data

Beta (β−) 47.66 11.61

Beta (β−) 111.69 9.0

Beta (β−) 149.35 79.4

Gamma 112.9498 6.17

Gamma 208.3662 10.36

2.8.3 Clinical Applications of 177Lu

177Lu include treatment of neuroendocrine tumors (NETs) where cellular receptors

An indirect method to produce 177Lu performs on the radiation of enriched

TESTS METHODS SPECIFICATIONS

2.10.3 Clinical applications

2.11 QUALITY CONTROL OF 68Ga

2.11.1 Quality Control Of 68Ga Obtained from a

radioisotope is conveniently availability from 68Ge/68Ga generator by decay of the

68Ge breakthrough: As 68Ge decays exclusively by electron capture to 68Ga, the

presence of 68Ge impurity in 68Ga eluate cannot be directly determined by

e Radiochemical purity: An aliquot of the 68GaCl3 eluted from the generator be

analysed by paper chromatography on a Whatman™ 3 mm chromatography paper (12 x

2.11.2 Regulatory Aspects Of Ge\Ga 68 Generator

2.11.3 Quality Control Of 68Ga Produced By Cyclotron

68Ga can be produced by small size biomedical cyclotrons by proton irradiation of

Clear and colourless solution

2.12.1 Biokinetic studies

For a new radiopharmaceutical, the determination of reference levels of irradiation and

2.13 Regulatory Aspects of Dose Calculations

In order to develop effective radiopharmaceuticals for therapy, it is essential to carefully

Licensed radiopharmaceuticals are to be used following the instructions and recommendations

4.2 Synthesis of FDG:

4.2.1 Step 1: Irradiation of 18O water with protons

4.2.2 Step 2: Extraction of [18F] fluoride the H2O18

4.2.4 Step 4: Labelling of the mannose triflate with the 18F

4.2.5 Step 5: Removal of the protective acetyl groups by hydrolysis to