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A three-part project was devised to investigate the origins of and potential methods to reduce the risk of occupational exposure to cytotoxic drugs. The first phase involved researching the current decontamination methods applied in UK hospital pharmacies, which manipulate cytotoxic drugs. The second phase evaluated practical decontamination methods, and the third phase investigated one intervention aimed at reducing or preventing contamination occurring in an isolator. A questionnaire was sent out to ASU managers in NHS hospital pharmacies to gain information about the disinfection and decontamination procedures and products used. The practical decontamination methods investigated were mechanical removal and degradation by detergents (pH range from 1.7 - 13.2) and cleaning agents, and degradation by vaporised hydrogen peroxide. Analytical methods were developed and validated to recover and quantify the amount of cytotoxic marker drug remaining after the decontamination tests carried out in phase two, and to recover and quantify cytotoxic surface contamination from various surfaces in phase three of this work. This composed an attempt to evaluate the effectiveness of a closed-system e.g. PhaSeal® device for fluid-transfer, in reducing contamination produced from the compounding of cytotoxic drugs in an isolator. The detergents and cleaning agents were effective in removing or reducing cytotoxic surface contamination. Alkaline detergents caused degradation of doxorubicin (maximum 81% at pH 13.2 after 1 hour exposure); the other detergents tested did not xi x degrade the cytotoxic drugs investigated. Exposure to vaporised hydrogen peroxide (1.6g min-1 for 2 hours) caused the degradation of cyclophosphamide (98.9%), 5-Fluorouracil (29.3%), doxorubicin (71.0%) and epirubicin (65.9%) when exposed in pharmaceutical diluents. The closed-system (PhaSeal®) device was effective in reducing contamination produced in an isolator from the compounding of cytotoxic drugs. The risk posed by handling and manipulation of cytotoxic drugs and products to the operator and the environment may be reduced, if not eliminated by considering additional approaches to the methods already in place. Firstly, the application of effective decontamination methods; and secondly, by using an effective closed-system, for example the PhaSeal® drug transfer device in a controlled environment.

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<p>During the last decades, chemotherapy with cytotoxic drugs has played a significant role in cancer therapy. It’s important to develop new anticancer drugs, and drug sensitivity testing in vitro can be used to find the right diagnosis for the newly developed substances.</p><p>The aim of this study was to investigate the cytotoxic activity of the new signal transduction modulators bortezomib, gefitinib and PKC412. The well-established substances cisplatin, cytarabine, doxorubicin and vincristin were investigated for comparison.</p><p>The activity of the cytotoxic drugs was analysed in human tumor samples from patients with ovarian carcinoma (n=16) and lymphoma (n=15) by using the Fluorometric Microculture Cytotoxicity Assay (FMCA). The testing of cellular drug resistance by FMCA was accomplished successfully in 33 out of the 34 samples (97%).</p><p>The results of this study indicated that the activity of cytotoxic drugs in tumor cells obtained from patients with ovarian carcinoma and lymphoma may be detected by the FMCA. It also suggested that bortezomib and gefitinib could represent promising agents for treatment of ovarian carcinoma and that PKC412 might be of less use for patients with this diagnose.</p>

During the last decades, chemotherapy with cytotoxic drugs has played a significant role in cancer therapy. It’s important to develop new anticancer drugs, and drug sensitivity testing in vitro can be used to find the right diagnosis for the newly developed substances. The aim of this study was to investigate the cytotoxic activity of the new signal transduction modulators bortezomib, gefitinib and PKC412. The well-established substances cisplatin, cytarabine, doxorubicin and vincristin were investigated for comparison. The activity of the cytotoxic drugs was analysed in human tumor samples from patients with ovarian carcinoma (n=16) and lymphoma (n=15) by using the Fluorometric Microculture Cytotoxicity Assay (FMCA). The testing of cellular drug resistance by FMCA was accomplished successfully in 33 out of the 34 samples (97%). The results of this study indicated that the activity of cytotoxic drugs in tumor cells obtained from patients with ovarian carcinoma and lymphoma may be detected by the FMCA. It also suggested that bortezomib and gefitinib could represent promising agents for treatment of ovarian carcinoma and that PKC412 might be of less use for patients with this diagnose.

Le déploiement d’outils de Contrôle de Qualité Analytique (CQA) intégrés à la boucle de soins apparaît comme un fort contributeur à la sécurisation du circuit des médicaments cytotoxiques en milieu de soin. Les techniques analytiques actuellement disponibles ont en commun d’être intrusives, de détruire une fraction des solutions thérapeutiques, d’exposer les personnels et de générer une filière spécifique d’élimination de déchets toxiques. En regard, de ces éléments, l’analyse non intrusive par Spectroscopie Raman (SR) est particulièrement innovante et en capacité d’améliorer significativement le cahier des charges technique du CQA. Le but de ce travail de thèse a été de procéder à une qualification opérationnelle de la SR dans le contexte du CQA hospitalier. Une attention particulière a été portée à la praticabilité de la nouvelle solution technique par SR, à son impact sur la sécurité et sur la sûreté des personnes et des biens ainsi qu’en terme environnemental. / The development of effective tools for the analytical quality control (AQC) of therapeutic objects (TO) appear to be a strong contributor to security of the cytotoxic drugs circuit in health care settings. Our goal is to ensure a high and stable quality in our pharmaceutical preparations for the benefit of patients and caregivers. Presently available analytical techniques have in common to be intrusive, destroying a fraction therapeutic solutions, exposing personal and generate specific toxic waste disposal. Compared to these, the non-intrusive analysis by Raman spectroscopy (RS) appears to us particularly innovative and has the capacity to significantly improve the specification of AQC technical specifications. The purpose of this work was to conduct an operational qualification of RS in the context of AQC. Special attention has been given to the feasibility of the new technical solution for SR, its impact on safety of persons and their working environment.