Optimization of production methods for gallium-68 PET radiopharmaceuticals in a hospital radiopharmacy

Le Roux, Johannes Stephanus (2020-12)

Thesis (PhD)--Stellenbosch University, 2020.

Thesis

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.

AFRIKAANSE OPSOMMING : Produksie van radiofarmaseutika vir menslike gebruik en navorsing geskied oor die algemeen in goed toegeruste kommersiële- of navorsingsfasiliteite wat meestal oor gevorderde toerusting vir die sintese en gehaltebeheer van radiofarmaseutika beskik. Kerngeneeskunde-afdelings is oor die algemeen geleë in hospitale en hul radiofarmasie fasiliteite beskik dikwels slegs oor beperkte ruimte en toerusting wat deeglike oorwegingvan produksiemetodes noodsaak. Die optimiseringsproses kan vereenvoudiging van ingwikkelde gehaltebeheerprosedures insluit deur gebruik te maak van minder komplekse toerusting en prosedures. Die doel van hierdie studie was om met behulp van 'n produkvoorbeeld, nl ubiquicidin wat met gallium-68 gemerk word, ondersoek na die belangrikste aspekte van radiofarmaseutiese sinteses in 'n betreklik eenvoudige opset te doen. Die peptied ubiquicidin word tans ondersoek om met die hulp van positron emissie tomografie (PET) infeksies in pasiënte op te spoor. Tot onlangs was die merking van ubiquicidin met gallium-68 hoofsaaklik gebaseer op ’n handmerkingsmetode. Handmerkingsmetodes word nie aanbeveel vir roetine produksie van radiofarmaseutika nie; enersyds weens probleme om aan vereistes vir goeie vervaardigingspraktyk te kan voldoen en andersyds weens ‘n hoër stralingsdosis wat werknemers ontvang. Hierdie nadele kan grootliks oorbrug word deur die gebruik van modules wat die merkingsmetdoes outomatiseer. Die navorsing in hierdie studie behels kortliks die volgende aspekte: • Outomatisering van ‘n handmerkingsmetode om ubiquicidin 29-41 met gallium-68 te merk • Optimisering van die sintese prosedure deur die gebruik van vry-radikaalinhibeerders • In-diepte vergelyking van die merkinsgeienskappe van die handmetodes teenoor dié van outomatiese metodes • Literatuurstudie na die toksisteit van HEPES in mense en diere om die gebruik daarvan as ’n buffer in die vervaardging van radiofarmaseutika in perspektief te stel • Ondersoek van dunlaagchromatografiemetodes vir die bepaling van radiochemiese suiwerheid van gallium-68 ubiquicidin Twee verskillende tipes outomatiese sintesemetodes is vir die doeleindes van hierdie studie ontwikkel. Optimisering van die merkinsgsproses is bewerkstellig deur die gebruik van ten minste twee vry-radikaalinhibeerders om die vorming van ongewenste onsuiwerhede te beperk. ′n Vergelyking van die merkinsgeienskappe van die handmerkingsmetode teenoor die outomatiese metodes dui daarop dat die outomatiese merkingsmetodes meer robuust en herhaalbaar is. Die literatuurstudie na die gebruik van HEPES in mense en diere dui daarop dat die toksisiteit van HEPES in mense moontlik deur die farmakopieë oorskat word. Die grense wat tans deur die farmakopieë voorgestel word mag dalk te streng wees. Die evaluering van verskeie dunlaagchromatografiemetodes dui daarop dat die huidige metode wat in die literatuur beskryf word die teenwoordigheid van ’n kolloïdale onsuiwerheid in die finale produk onderskat. Al die ander metodes wat in hierdie studie ondersoek is kon nie hierdie onsuiwerheid van die gemerkte produk onderskei nie. Hierdie aspek beklemtoon die belangrikheid van van ’n suiweringstap in die merkingsprosedure om die teenwoordigheid kolloïdale onsuiwerheid in die finale produk te voorkom. Die werk wat in hierdie studie vervat word skep ’n belangrike grondslag vir toekomstige optimisering van produksiemetodes in ’n kliniese omgewing. Die studie kan verder ook deur ander kerngeneeskunde afdelings as riglyn gebruik word in die optimisering van produksiemetodes van radiofarmseutika.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/109273
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