Nuclear Medicine

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Implementation of guidelines on hospital radiopharmacy in low-income settings
(Stellenbosch : Stellenbosch University, 2020-12) Ekoume, Fany Pricile; Rubow, Sietske Margarete; Boersma, Hendrikus H.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medical Imaging and Clinical Oncology. Nuclear Medicine.
ENGLISH SUMMARY : Although radiopharmacy is more than 50 years old, it is still in a stage of rapid development. This dissertation focuses on quality issues in radiopharmacies in developing countries. Guidelines for radiopharmacy practice in many countries prescribe complex facilities, especially air handling units, and extensive quality assurance and documentation requirements. In developing countries, these guidelines are currently not always met. In numerous countries in Africa, enforcement of the international guidelines would lead to closure of radiopharmacies, and consequently, loss of Nuclear Medicine services. The question arises what the consequences of not meeting the requirements of the guidelines are, and if practice can be improved without major expenditure. This study considered certain aspects of Good Radiopharmacy Practice (GRP) recommendations and collected information from both a relatively well-equipped facility at Tygerberg Hospital (TBH) in South Africa, and a more basic radiopharmacy facility at Yaoundé General Hospital in Cameroon (YGH) to investigate the conditions that will ensure safe and effective products. Factors assessed include efficacy and microbial safety of the radiopharmaceuticals, with some comparison to a state-of-the-art Good Manufacturing Practice (GMP) compliant radiopharmacy at the University Medical Centre Groningen (UMCG) in the Netherlands. An adapted version of the Quality Management Audits in Nuclear Medicine (QUANUM) tool, tailored for the radiopharmacy context, was used to determine the status of practice in the two African radiopharmacies. Once the current situation and product quality in these radiopharmacies was determined, basic, low-cost interventions to minimise deficiencies were implemented at YGH and the effects of the interventions were assessed. Where the necessary level of safety and efficacy could not be met with currently available systems despite interventions, this was reported. The efficacy of radiopharmaceuticals depends on their radiochemical purity. As lack of validation of analytical methods was one of the shortcomings noted in the YGH audit, experimentally validating a cost-effective radiochromatography method to be used at YGH was the first step of corrective actions implemented. As the provision of clean air and maintenance of air handling systems and equipment require a large budget, special emphasis was placed in three further chapters of the dissertation on assessment of microbial contamination of products, and measures to ensure sterility of products. At YGH, we reached better control of microbiological air quality. This was achieved by the implementation of simple microbiological air sampling methods, and subsequent introduction of hygienic and procedural improvements. Sterility testing of SPECT radiopharmaceuticals showed a low contamination rate at both TBH and YGH. Nevertheless, preparing radiopharmaceuticals in a well-maintained laminar air flow cabinet is recommended in order to reduce the risk of contamination of products by airborne microorganisms. The serious consequences that could arise from not meeting GRP requirements, include transmission of microbial infection to patients or administering radiochemically impure products. This dissertation presents the first work evaluating an affordable approach of the implementation of GRP in sub-Saharan Africa. It is highly recommended to all radiopharmacies in the developing world to adapt GRP in their context and to implement an optimised quality assurance programme, striving for continuous improvement.
Investigation into various aspects of radiolabelling somatostatin peptide derivatives with 68Ga eluted from a SnO2-based 68Ge/68Ga generator
(Stellenbosch : Stellenbosch University, 2018-03) Prince, Deidre Mabel; Rubow, Sietske Margarete; Rossouw, Daniel Dutoit; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medical Imaging and Clinical Oncology. Nuclear Medicine.
ENGLISH SUMMARY : 68Ge/68Ga generators ensure the supply of 68Ga for positron emission tomography (PET), for instance for somatostatin receptor imaging with 68Ga-DOTA-labelled somatostatin analogues. There are various generators available and their eluates are processed differently for radiolabelling of peptides. The objectives of this study were to investigate various aspects of the elution characteristics of the generator, to optimize labelling conditions using different eluate processing techniques such as fractionation and cation exchange chromatography and to develop user-friendly kit formulations. This study was approved by the Stellenbosch University Health Research Ethics Committee and permission was granted for the experimental work to be conducted at iThemba LABS. Elution efficiencies were determined using different HCl concentrations (0.2 M – 1.0 M). Metal analysis and 68Ge breakthrough determination were performed on eluates. Radiolabelling parameters were optimized, using fractionated eluates and different DOTA-peptide masses (15 to 50 μg) at pH 3.5 – 4.0 in sodium acetate buffer. Different heating times and heating methods and the influence of various periods of non-elution of the generator on radiolabelling results were investigated. Cationic resins were investigated for eluate processing. Radiolabelling parameters, using cationic resin-processed eluates, were optimized. Labelling was conducted at various pH values, using different quantities of buffer. DOTA-peptide kits for both fractionated and resin-processed eluates were developed and tested for sterility, endotoxin content and stability. Radiochemical yields, radiolabelling efficiency and radiochemical purity of 68Ga-DOTA-peptides were determined. The elution efficiency of the generator increased with an increase in the concentration of HCl eluent. The 68Ge breakthrough increased dramatically at 0.8 M HCl. Most metal contaminants were lowest when eluting with 0.2 M HCl and the Zn content increased with the increase in HCl concentration. The eluent of choice for the SnO2-based generator was confirmed to be 0.6 M HCl. For radiolabelling, 35 μg DOTA-peptide (9.2 – 9.4 μM) was the most favourable. Extended heating times and heating method did not significantly impact on the radiolabelling. The radiolabelling efficiencies were consistently above 90 % even after 3 weeks of non-elution of the generator, but radiochemical yields dropped after 7 days. DOTA-peptide kits for fractionated eluates were successfully developed and the radiolabelling quality was found to be superior over peptide stock solutions. A radiolabelling method using a cationic exchange resin was successfully adapted for the SnO2 generator. 68Ga was efficiently adsorbed on a Bond Elut SCX (100 mg) cartridge and desorbed by acidified solutions of NaCl. The SCX resin effectively removed about 98 % of deliberately “spiked” metals from the 68Ga eluate. An optimized labelling method based on the use of SCX-purified eluates was developed, producing radiochemical yields of almost 85 % and lead to the successful formulation of DOTATATE kits. The quality was found to be suitable over a 3-month period. In conclusion, a kit type labelling procedure, using cationic resin purified 68Ga eluates, provides the most practical method to produce 68Ga-labelled DOTA-peptides.
Monitoring various eluate characteristics of the iThemba LABS SnO2-based 68Ge/68Ga generator over time and validation of quality control methods for the radiochemical purity assessment of 68Ga-labelled DOTA peptide formulations
(Stellenbosch : Stellenbosch University, 2017-03) Davids, Claudia Ruby; Rubow, Sietske Margarete; Rossouw, Daniel; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medical Imaging and Clinical Oncology. Nuclear Medicine
ENGLISH SUMMARY : PET imaging with gallium-68 (68Ga) has become widely used due to the availability of 68Ge/68Ga generators and DOTA-derivatised peptide ligands for radiolabelling. The purpose of this study was to monitor the eluate of two iThemba LABS 68Ge/68Ga generators over a period of 12 months to ascertain whether all quality parameters of the 68Ga eluate remained stable and to validate different analytical methods used to determine the radiochemical purity of 68Ga-labelled peptides. Two 1850 MBq (50 mCi) generators were eluted daily with 0.6 M HCl and metal contaminants, 68Ge breakthrough, 68Ga yield, pH, sterility and endotoxin concentrations were determined on a monthly basis. The radiochemical purity of 68Ga-labelled peptides was ascertained using high performance liquid chromatography (HPLC) and instant thin layer chromatography (iTLC). iTLC experiments were performed using both dried and undried iTLC plates. iTLC was also carried out on labelled peptide solution that was spiked with 68GaCl3. These results were also compared with those using HPLC. After 12 months the 68Ga yields, total metal contaminants, sterility and endotoxin concentration remained within European Pharmacopoeial limits. The 68Ge breakthrough increased as the generator aged. This can however be minimised by fractionated elution and post-labelling processing of the eluate by anion or cation exchange chromatography. Separation between 68GaCl3 and 68Ga-labelled peptides was obtained using both 0.1 M citrate buffer pH 5.0 (mobile phase 1) and 1 M ammonium acetate : methanol (1:1) (mobile phase 2). The results also showed that the distribution of radioactivity on the iTLC strip could be determined using a dose calibrator when a TLC scanner is not available. Experiments performed using both undried and dried iTLC-SG chromatography paper, demonstrated that despite the statistically significant difference between the sets of results, in practice either undried or dried iTLC may be used. When purified 68Ga-labelled peptides were spiked with 2% of 68GaCl3, separation between the two was obtained on both HPLC and iTLC. However, iTLC underestimated and HPLC overestimated 68GaCl3 content. Of the two iTLC methods investigated, the method using mobile phase 2 was able to separate colloidal 68Ga impurities from the 68Ga-labelled peptides while the method using mobile phase 1 and the HPLC method could not. In conclusion, the iThemba LABS 68Ge/68Ga generator can be considered stable and of use for up to one year after its manufacture. Both the iTLC method and the HPLC method could detect 68GaCl3 amounts less than 2%. The pharmacopoeia states that 68Ga must be less than 3 % on iTLC and less than 2 % on HPLC. Either dried or undried iTLC strips can be used and if a radio-TLC scanner is not available, the iTLC strips developed with mobile phase 1 can be cut at a suitable distance from the origin and the activity on each section can be read in a dose calibrator. iTLC chromatography using ammonium acetate/methanol seems to be the optimal system for routine analysis of 68Ga labelled DOTA-peptides, as it separates both 68GaCl3 and colloidal impurities from the labelled peptides and is a fast and easy technique.
Optimization of production methods for gallium-68 PET radiopharmaceuticals in a hospital radiopharmacy
(Stellenbosch : Stellenbosch University, 2020-12) Le Roux, Johannes Stephanus; Rubow, Sietske Margarete
ENGLISH SUMMARY : Production of radiopharmaceuticals intended for human use and research purposes is generally performed in well-equipped commercial or research facilities that usually have access to advanced equipment for the synthesis and quality control of radiopharmaceuticals. Nuclear Medicine departments are in most cases situated in hospitals. Radiopharmacies in these departments usually have limited space and equipment which necessitates careful consideration of suitable production methods. Optimization may include methods to simplify quality control procedures through the use of less sophisticated equipment and procedures. The purpose of this study was to demonstrate how to optimize production methods in an environment with limited resources using ubiquicidin labelled with gallium-68 as an example. The peptide ubiquicidin is currently investigated for localization of infections in patients using positron emission tomography (PET). Until recently, labelling ubiquicidin with gallium-68 was limited to a manual labelling method. Manual labelling methods are not recommended for the routine production of radiopharmaceuticals because of difficulty to comply with Good Manufacturing Practice (GMP). Manual labelling methods can also result in high radiation exposure to personnel. These disadvantages can be addressed by automation of production methods. The research conducted in this study shortly entails the following aspects: •Automation of a manual labelling method of ubiquicidin with gallium-68 •Optimization of the synthesis methods using radical scavengers •In-depth comparison of the labelling characteristics of the manual method to that of theautomated methods •Conducting a literature search into the toxicity of HEPES in humans and animals in order toclarify its use as a buffering agent in the labelling of radiopharmaceuticals • Investigating thin-layer chromatography as method to determine the radiochemical purity of gallium-68 ubiquicidin Two different automated synthesis methods were developed in this study. Optimization of the labelling methods was achieved by adding free-radical scavengers to reduce the formation of impurities. A comparison of the labelling characteristics of the manual labelling method with the automated methods showed that the results obtained with automated methods were more robust and repeatable. The literature search into the toxicity of HEPES showed that its toxicity in humans and animals may be overestimated by pharmacopoeias. The current limits applied by pharmacopoeias may be too strict. An evaluation of several thin-layer chromatography methods indicated that the method currently described in the literature may underestimate the presence of colloidal impurities in the final product. None of the other methods investigated in this study could distinguish the colloidal impurity from the labelled product. This aspect highlights the need for a final purification step to reduce the presence of colloidal impurities in the final product. The work presented in this study creates an important basis for optimization of production methods in a clinical environment. The study can further serve as a guideline to other nuclear medicine departments for optimization of radiopharmaceutical production methods.
Validation of radiochemical purity analysis methods used in two tertiary public hospitals in South Africa
(Stellenbosch : Stellenbosch University, 2016-03) Mambilima, Nelia; Rubow, Sietske Margarete; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medical Imaging and Clinical Oncology. Nuclear Medicine.
ENGLISH SUMMARY : Radiopharmaceutical kits are supplied by manufacturers with package inserts containing information about the kit including validated methods of preparation and radiochemical purity (RCP) analysis. Validated analytical methods are also described in pharmacopoeial monographs. However the information provided is not always complete or practical and in a hospital setting it can be difficult to select and perform adequate RCP testing on the prepared radiopharmaceuticals. This situation has led to modifications or substitution for much quicker, simplified, safe or cost-effective analytical procedures. A number of these procedures have been proposed in published literature and have been incorporated in some hospital settings including radio pharmacies in Africa. Since the responsibility of any method that deviates from the official pharmacopoeial or manufacturer’s method rests with the end user, this study was aimed to determine whether appropriate validation procedures based on the Q2A and Q2B guidelines of the International Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) are feasible for use in a resource limited environment, which pertains in most hospital radio pharmacy settings in Southern Africa. A further aim was to develop a prototype protocol for validation of analytical procedures in a hospital radio pharmacy setting. In an attempt to undertake a full analytical method validation, eight validation parameters described in the ICH guidelines were selected for the current study namely specificity, accuracy, precision (repeatability and intermediate precision), linearity, range, limit of detection, limit of quantitation and robustness. To undertake the validation exercise, fast RCP test methods for Tc-99m sestamibi involving the use of Whatman 31ET and Schleicher and Schuell chromatography paper were used. Locally procured Macherey-Nagel (MN) Alox N aluminium oxide TLC strips were intended as control method as the Baker-Flex aluminium oxide TLC strips described in the manufacturer’s instructions could not be sourced. All the tests were performed in triplicate and results were compared. A limited number of tests was also performed on Baker-Flex TLC strips to compare with the results of the substitute MN Alox method. The radiochemical components namely Tc-99m sestamibi, Tc-99m colloid and pertechnetate that were prepared in house and were assumed to be 100 % pure, were each tested on the chromatography strips. Samples containing mixtures of varying concentrations of the radiochemical components were also tested on all the strips. Radiochemical purity test results of sestamibi samples without any added impurities were 99.8 % ± 0.0 % for Macherey-Nagel Alox TLC, 99.5 % ± 0.1 % for Whatman 31ET paper and 99.3 % ± 0.2 % for Schleicher and Schuell paper chromatography strips. When Tc-99m pertechnetate and Tc-99m colloid were added to Tc-99m sestamibi as impurities after completion of kit reconstitution, the values for sestamibi were in all cases higher than the calculated RCP. These higher results could have been due to binding of the added technetium to the sestamibi. Another possibility would be that another technetium compound was formed after mixing the already prepared radiochemical components. This new impurity then co-migrated with the Tc-99m sestamibi on the chromatography strips. The unknown impurity could not be isolated or quantified. This impurity could not be proved to be Tc-99m pentamibi, as it was not possible to prepare this radiochemical component in-house and hence all the analytical methods lacked specificity. The MN Alox test method showed exceptionally high values for sestamibi due to co-elution of the free pertechnetate with sestamibi in addition to the unknown impurity. As a result, the MN Alox RCP test method could not be used as a reference standard. The poor agreement between the nominal (calculated) and observed results had a negative effect on the accuracy and linearity over the range that was selected of all the three analytical procedures. Apart from meeting the acceptance criteria for repeatability and intermediate precision, all three analytical methods were also noted to be robust. For the radiochromatogram scanner, the limit of detection was 59 counts while the limit of quantitation was 177 counts for the scanning speed and distance used. In conclusion, all the eight ICH validation parameters are essential when validating a RCP test method. Also, validating an analytical procedure in a hospital setting is possible once some important prerequisites are met, such as availability of staff trained in radiopharmacy or radiochemistry, availability of specified materials for the reference procedure or control experiments, in house preparation of reference standards, and a template validation protocol for thin layer chromatography (TLC) and paper chromatography. Availability of specialized equipment such as a high performance liquid chromatography (HPLC)system for radiopharmaceuticals that have impurities other than free pertechnetate and colloid, is also a requirement, but HPLC is not currently available in public sector Radiopharmacies in South Africa.

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Browsing Nuclear Medicine by browse.metadata.advisor "Rubow, Sietske Margarete"

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