Position paper to facilitate patient access to radiopharmaceuticals: considerations for a suitable pharmaceutical regulatory framework.

BACKGROUND: Nuclear medicine has made enormous progress in the past decades. However, there are still significant inequalities in patient access among different countries, which could be mitigated by improving access to and availability of radiopharmaceuticals. MAIN BODY: This paper summarises major considerations for a suitable pharmaceutical regulatory framework to facilitate patient access to radiopharmaceuticals. These include the distinct characteristics of radiopharmaceuticals which require dedicated regulations, considering the impact of the variable complexity of radiopharmaceutical preparation, personnel requirements, manufacturing practices and quality assurance, regulatory authority interfaces, communication and training, as well as marketing authorisation procedures to ensure availability of radiopharmaceuticals. Finally, domestic and regional supply to ensure patient access via alternative regulatory pathways, including in-house production of radiopharmaceuticals, is described, and an outlook on regulatory challenges faced by new developments, such as the use of alpha emitters, is provided. CONCLUSIONS: All these considerations are an outcome of a dedicated Technical Meeting organised by the IAEA in 2023 and represent the views and opinions of experts in the field, not those of any regulatory authorities.

Highlight selection of radiochemistry and radiopharmacy developments by editorial board.

BACKGROUND: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biannual highlight commentary to update the readership on trends in the field of radiopharmaceutical development. MAIN BODY: This selection of highlights provides commentary on 21 different topics selected by each coauthoring Editorial Board member addressing a variety of aspects ranging from novel radiochemistry to first-in-human application of novel radiopharmaceuticals. CONCLUSION: Trends in radiochemistry and radiopharmacy are highlighted. Hot topics cover the entire scope of EJNMMI Radiopharmacy and Chemistry, demonstrating the progress in the research field in many aspects.

The relative contribution of photons and positrons to skin dose in the handling of PET radiopharmaceuticals.

BACKGROUND: Despite recommendations to use syringe and vial shields to reduce exposure of the hands of staff when manipulating PET radiopharmaceuticals, operators sometimes prefer to work without shields, believing that the faster handling limits the equivalent dose. The aim of this work is to show that this approach does not properly consider the contribution of positrons to the dose. MATERIALS AND METHODS: Using the Varskin+ code, skin doses were calculated for syringes of various sizes, filled with 18F, 11C or 68Ga solution. Syringes without shielding, or shielded with 2 mm and 10 mm of tungsten were considered. RESULTS: Dose rate values in mSv/s per MBq, averaged on a 1 cm2 surface at a depth of 0.07 mm were calculated for all the above conditions. For example, in the case of 3 mL 18F syringe at 1 mm from the skin, the dose rate without shielding is 1.32E-02 and 8.63E-04 for positrons and photons respectively. For 11C, the corresponding dose rates are 4.70E-02 and 8.90E-04 respectively, and for 68Ga, 8.52E-02 and 9.48E-04. CONCLUSIONS: Our results show that the dose due to positrons is the principal component of skin irradiation, by a factor of 3-100, depending on the conditions. The use of shields for syringes and vials is necessary to avoid unjustified skin exposures, that may challenge dose limits. In our opinion, automatic systems for dispensing and allowing injection with shielded syringes, or automatic injectors, are economically justified and should be adopted in PET.

Radiation Safety and Accidental Radiation Exposures in Nuclear Medicine.

Medical radiation accidents and unintended events may lead to accidental or unintended medical exposure of patients and exposure of staff or the public. Most unintended exposures in nuclear medicine will lead to a small increase in risk; nevertheless, these require investigation and a clinical and dosimetric assessment. Nuclear medicine staff are exposed to radiation emitted directly by radiopharmaceuticals and by patients after administration of radiopharmaceuticals. This is particularly relevant in PET, due to the penetrating 511 keV γ-rays. Dose constraints should be set for planning the exposure of individuals. Staff body doses of 1-25 µSv/GBq are reported for PET imaging, the largest component being from the injection. The preparation and administration of radiopharmaceuticals can lead to high doses to the hands, challenging dose limits for radionuclides such as 90Y and even 18F. The risks of contamination can be minimized by basic precautions, such as carrying out manipulations in purpose-built facilities, wearing protective clothing, especially gloves, and removing contaminated gloves or any skin contamination as quickly as possible. Airborne contamination is a potential problem when handling radioisotopes of iodine or administering radioaerosols. Manipulating radiopharmaceuticals in laminar air flow cabinets, and appropriate premises ventilation are necessary to improve safety levels. Ensuring patient safety and minimizing the risk of incidents require efficient overall quality management. Critical aspects include: the booking process, particularly if qualified medical supervision is not present; administration of radiopharmaceuticals to patients, with the risk of misadministration or extravasation; management of patients' data and images by information technology systems, considering the possibility of misalignment between patient personal data and clinical information. Prevention of possible mistakes in patient identification or in the management of patients with similar names requires particular attention. Appropriate management of pregnant or breast-feeding patients is another important aspect of radiation safety. In radiopharmacy activities, strict quality assurance should be implemented at all operational levels, in addition to adherence to national and international regulations and guidelines. This includes not only administrative aspects, like checking the request/prescription, patient's data and the details of the requested procedure, but also quantitative tests according to national/international pharmacopoeias, and measuring the dispensed activity with a calibrated activity meter prior to administration. In therapy with radionuclides, skin tissue reactions can occur following extravasation, which can result in localized doses of tens of Grays. Other relevant incidents include confusion of products for patients administered at the same time or malfunction of administration devices. Furthermore, errors in internal radiation dosimetry calculations for treatment planning may lead to under or over-treatment. According to literature, proper instructions are fundamental to keep effective dose to caregivers and family members after patient discharge below the Dose constraints. The IAEA Basic Safety Standards require measures to minimize the likelihood of any unintended or accidental medical exposures and reporting any radiation incident. The relative complexity of nuclear medicine practice presents many possibilities for errors. It is therefore important that all activities are performed according to well established procedures, and that all actions are supported by regular quality assurance/QC procedures.

Highlight selection of radiochemistry and radiopharmacy developments by editorial board.

BACKGROUND: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biyearly highlight commentary to update the readership on trends in the field of radiopharmaceutical development. RESULTS: This commentary of highlights has resulted in 21 different topics selected by each member of the Editorial Board addressing a variety of aspects ranging from novel radiochemistry to first in man application of novel radiopharmaceuticals. Also the first contribution in relation to MRI-agents is included. CONCLUSIONS: Trends in (radio)chemistry and radiopharmacy are highlighted demonstrating the progress in the research field being the scope of EJNMMI Radiopharmacy and Chemistry.

The use of HEPES-buffer in the production of gallium-68 radiopharmaceuticals - time to reconsider strict pharmacopoeial limits?

HEPES (4-(2-hydroxyethyl) piperazine-1-ethanesulfonic acid) is a buffer that is used in the radiolabelling of gallium-68 compounds. The beneficial effects of HEPES on molar activity in bioconjugates have been well described. Current strict regulations on the HEPES content in radiopharmaceuticals limit its use when intended for parenteral administration.This short communication summarizes data from the literature on the toxicity of HEPES in dogs after intravenous infusion and the subsequent use in humans. We also highlight the use of HEPES in an FDA labelled intravenous drug formulation. Regulatory institutions may consider this data to review current strict limits.

A comparison of labelling characteristics of manual and automated synthesis methods for gallium-68 labelled ubiquicidin.

Gallium-68 labelled 1,4,7-triazacyclononane-1,4,7-triacetic acid ubiquicidin (NOTA-UBI) is currently investigated as a PET radiopharmaceutical for the imaging of infections. The aim of this study was to compare the labelling characteristics of an optimized manual radiosynthesis method with those of optimized automated synthesis methods. Data from this study suggest that automated radiosynthesis of [68Ga]Ga-NOTA-UBI provides a higher degree of robustness and repeatability than the manual method. Our results also suggest that for our full-scale automated synthesis, radical scavengers should be considered to reduce radiolysis. Automated synthesis methods have the advantage of markedly reducing radiation exposure to operators. Standardised automation also makes the synthesis more reliably compliant with Good Manufacturing Practice guidelines.

Production of [68 Ga]Ga-PSMA: Comparing a manual kit-based method with a module-based automated synthesis approach.

The labeling of peptides with gallium-68 is often initially performed by manual labeling, but with high clinical demand, other alternatives are needed. Cold-kits or automated synthesis are viable options for standardized methods and deemed pharmaceutically more acceptable. This study compares these [68 Ga]Ga-PSMA-11 production methods. Data from 40 kit-based and 40 automated syntheses of [68 Ga]Ga-PSMA-11 were analyzed. Pre-set criteria were evaluated including radiochemical purity, radionuclidic purity, chemical purity, physiological acceptability and sterility. The operator time and radiation dose received were measured. The robustness and repeatability of each method were assessed and a comparison of the running costs of each method is also provided. For both the methods all the analyzed products met the release criteria. No differences were found in radiochemical purity, radiochemical identity, radionuclidic purity, and sterility. However, radiochemical yield and apparent molar activity showed significant differences. For both methods, whole body radiation exposure to operators was lower than with manual labeling (25 - 40 µSv). The exposure during kit-based labeling (14.5 ± µSv) was seven times higher than that of automated synthesis (2.05 ± 0.99 µSv). The automated synthesis was the more expensive method. Both methods are sound alternatives to manual synthesis and offer higher quality, better radiation protection and a more reliable manufacturing of radiopharmaceuticals.

Optimization of a Labeling and Kit Preparation Method for Ga-68 Labeled DOTATATE, Using Cation Exchange Resin Purified Ga-68 Eluates Obtained from a Tin Dioxide 68Ge/68Ga Generator.

PURPOSE: The aim of this study was to optimize a radiolabeling method using cationic processed Ga-68 eluates from a SnO2-based 68Ge/68Ga generator, followed by the development of DOTA-Tyr3-Thre8-octreotide (DOTATATE) kits. PROCEDURES: Diluted generator eluates were adsorbed on a SCX resin and desorbed with acidified 5 M NaCl solution. Optimized labeling conditions were determined by variation of pH, using 35 µg DOTATATE and sodium acetate buffer. DOTATATE kits were developed based on optimized radiolabeling conditions, were labeled, and evaluated. RESULTS: Optimized labeling conditions resulted in a radiolabeling efficiency of around 99 % and radiochemical yield of almost 85 %. Different kit preparation methods did not significantly influence the radiolabeling results. Kits were found to be stable over 3 months. CONCLUSION: A labeling method using SCX-processed Ga-68 eluates was optimized. DOTATATE kits specifically for these SCX-processed Ga-68 eluates were successfully formulated. A post-labeling Sep-Pak C18 purification should be optional.

Development and Evaluation of User-Friendly Single Vial DOTA-Peptide Kit Formulations, Specifically Designed for Radiolabelling with 68Ga from a Tin Dioxide 68Ge/68Ga Generator.

PURPOSE: This study was aimed to develop single vial 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-peptide kits to be used with fractionated eluates from a SnO2-based 68Ge/68Ga generator. PROCEDURES: Kits were formulated with 35 µg DOTA-Tyr3-Thre8-octreotide, DOTA-[Tyr3]-octreotide and DOTA-[NaI3]-octreotide (DOTATATE, DOTATOC and DOTANOC) and sodium acetate powder, vacuum-dried and stored at -20 °C for up to 12 months. Labelling of the kits was carried out with 2 ml 68Ga eluate. Comparative labelling was carried out using aqueous DOTA-peptide stock solutions kept frozen at -20 °C for up to 12 months. RESULTS: The quality of the kits was found to be suitable over a 1-year storage period (pH, sterility, endotoxin content, radiolabelling efficiency and radiochemical yields of 68Ga-labelled DOTA-peptides). Radiochemical yields ranged from 73 to 83 %, while those obtained from stock solutions from 64 to 79 %. No significant decline in kit labelling yields was observed over a 12-month storage period. CONCLUSION: The single vial kit formulations met the quality release specifications for human administration and appear to be highly advantageous over using peptide stock solutions in terms of stability and user-friendliness.

Is there a role for 99mTc-HMPAO leucocyte scintigraphy in infective endocarditis?

Infective endocarditis is an important disease in developing countries. A combination of clinical findings, typical organisms cultured from blood, and specific echocardiographic features are used to establish the diagnosis. The diagnosis is often difficult because cultures are not always positive and transthoracic echocardiography lacks sensitivity and specificity, leading to delayed treatment or inappropriate therapy. As (99m)Tc-HMPAO-labeled leucocyte scintigraphy is used routinely to evaluate patients with suspected infectious processes, it was postulated that this technique might also aid in the diagnosis of infective endocarditis in patients with underlying chronic rheumatic heart disease or other valvular disease. Six patients were referred for (99m)Tc-HMPAO-labeled leucocyte scintigraphy. The white blood cells were labeled according to standard procedures. Whole-body planar imaging and single photon emission tomography of the chest area, with imaging at 30 minutes, 3 hours and 24 hours after the administration of the labeled leucocytes, were performed on all patients. All the scintigrams were negative. The reasons for the negative findings are not entirely clear, but probably reflect the pathological nature of vegetations, which consist mainly of masses of fibrin, clotted platelets and blood cell debris, containing the causative organisms. Leucocytes do not play a major role in the pathological process. Although only six patients were studied, it appears that (99m)Tc-HMPAO leucocyte scintigraphy is of little value in the evaluation of patients with infective endocarditis. A study after the administration of radiolabelled antibiotics may be of greater value and should be considered in these patients.