Browsing by Author "Mambilima, Nelia"

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    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.