The project described in this thesis was carried out in the Quality Control and Analytical Development laboratory of the PDS (Pharmaceutical Development Services) department at Thermo Fisher Scientific, Monza site. The drug PTH-425 is a therapeutic anticancer vaccine composed of two mRNA fragments (PTH-01 and PTH-02) encapsulated in lipid nanoparticles (LNPs). The pharmaceutical product is administered via intramuscular injection and is designed to treat uterine leiomyosarcoma (LMS), a malignant tumour whose diagnosis is complicated by symptoms that overlap whit those of more common benign fibroids. To evaluate the impact of a new pharmaceutical product on the manufacturing plant, a technical document is prepared to assess the characteristics and properties of its individual components. This evaluation aims to determine whether the validated cleaning methods for the specific production line can remove any product residues. The assessment included in the technical document identifies the worst-case component (active ingredient or excipient of the formulation) on which the cleaning validation should be performed. For the pharmaceutical product PTH-425, this component was identified as the cholesterol constituting the lipid nanoparticles (LNPs). The objective of this thesis is to outline and present the results obtained from the validation of an analytical cleaning method for the determination of cholesterol residues on pharmaceutical equipment. The cleaning verification procedures adopted at the manufacturing site must ensure the removal of unwanted residues below a predefined concentration limit. This approach minimizes the risk of cross-contamination between different pharmaceutical products during production. Two sampling techniques are used for surface sampling on the production line: the swab technique and the rinse technique. As established by ICH guidelines, the analytical parameters to be evaluated during method validation include: accuracy, precision (repeatability and intermediate precision), specificity, limit of quantification (LOQ), linearity, range, and robustness. In the context of cleaning method validation, it is also necessary to verify and validate the sampling techniques (swab and/or rinse where applicable). The analytical technique selected for validation is UHPLC (Ultra High Performance Liquid Chromatography) equipped with a CAD detector. This technique allows the separation and quantification of cholesterol residues in the analyzed solutions based on the resulting chromatogram. As reported in the thesis, the results obtained during the validation of the analytical cleaning method meet the acceptance criteria established for all tests performed, in compliance with ICH requirements and the procedure is considered suitable for GMP use in the QC PDS laboratory at Thermo Fisher Scientific, Monza site.
Il progetto descritto nella tesi è stato svolto presso il laboratorio di controllo qualità e sviluppo analitico del reparto PDS (Pharmaceutical Development Services) dell’azienda farmaceutica Thermo Fisher Scientific del sito di Monza. Il farmaco PTH-425 è un vaccino terapeutico antitumorale, composto da due frammenti di mRNA (PTH-01 e PTH-02) incapsulati in nanoparticelle lipidiche (LNPs). Il prodotto farmaceutico viene somministrato mediante infusione intramuscolare ed è progettato per trattare il leiomiosarcoma uterino (LMS), un tumore maligno la cui diagnosi è resa complicata da sintomi comparabili ai più comuni fibromi benigni. Allo scopo di valutare l’impatto di un nuovo prodotto farmaceutico sull’impianto, viene redatto un documento volto a valutare le caratteristiche e le proprietà dei suoi singoli componenti, al fine di valutare se i metodi di lavaggio (cleaning) validati per la specifica linea produttiva siano in grado di rimuovere qualsiasi residuo del prodotto. La valutazione inclusa nel documento tecnico individua il componente worst-case (attivo o eccipiente della formulazione) su cui eseguire la convalida dell’attività di cleaning, che nel prodotto farmaceutico PTH-425 viene identificato nel colesterolo costitutivo delle nanoparticelle lipidiche (LNPs). L’obiettivo della presente tesi è delineare ed esporre i risultati ottenuti dall’attività di convalida del metodo analitico di cleaning per la determinazione dei residui di colesterolo su impianti farmaceutici. Le procedure di cleaning verification, adottate dal sito produttivo, devono garantire la rimozione di residui indesiderati al di sotto di un determinato livello di concentrazione prestabilito. In questo modo viene ridotto il rischio di cross-contaminazione tra prodotti farmaceutici differenti durante la produzione. Per il campionamento delle superfici sulla linea produttiva vengono utilizzate due tecniche di campionamento: la tecnica swab e la tecnica rinse. Come stabilito dalle linee guida ICH, i parametri analitici da valutare durante l’attività di convalida di un metodo analitico sono: accuratezza, precisione (ripetibilità e precisione intermedia), specificità, limite di quantificazione (LOQ), linearità, range e robustezza. Nell’ambito della convalida di un metodo analitico di cleaning è necessario anche verificare e convalidare le tecniche di campionamento (swab e/o rinse dove applicabile). La tecnica analitica scelta per la convalida è una tecnica UHPLC (Ultra High Performance Liquid Chromatography) equipaggiata con rilevatore CAD. La tecnica consente di separare e quantificare i residui di colesterolo nelle soluzioni analizzate tramite il cromatogramma ottenuto. Come riportato nell’elaborato, i risultati ottenuti durante la convalida del metodo analitico di cleaning soddisfano i criteri di accettazione stabiliti per tutti i test eseguiti rispettando i requisiti ICH e la procedura viene ritenuta idonea per l’utilizzo GMP nel laboratorio QC PDS presso il sito di Thermo Fisher Scientific di Monza.
Convalida di un Metodo Analitico di Cleaning per la Determinazione dei Residui di Colesterolo su Impianti Farmaceutici
GELOSA, LORENZO
2024/2025
Abstract
The project described in this thesis was carried out in the Quality Control and Analytical Development laboratory of the PDS (Pharmaceutical Development Services) department at Thermo Fisher Scientific, Monza site. The drug PTH-425 is a therapeutic anticancer vaccine composed of two mRNA fragments (PTH-01 and PTH-02) encapsulated in lipid nanoparticles (LNPs). The pharmaceutical product is administered via intramuscular injection and is designed to treat uterine leiomyosarcoma (LMS), a malignant tumour whose diagnosis is complicated by symptoms that overlap whit those of more common benign fibroids. To evaluate the impact of a new pharmaceutical product on the manufacturing plant, a technical document is prepared to assess the characteristics and properties of its individual components. This evaluation aims to determine whether the validated cleaning methods for the specific production line can remove any product residues. The assessment included in the technical document identifies the worst-case component (active ingredient or excipient of the formulation) on which the cleaning validation should be performed. For the pharmaceutical product PTH-425, this component was identified as the cholesterol constituting the lipid nanoparticles (LNPs). The objective of this thesis is to outline and present the results obtained from the validation of an analytical cleaning method for the determination of cholesterol residues on pharmaceutical equipment. The cleaning verification procedures adopted at the manufacturing site must ensure the removal of unwanted residues below a predefined concentration limit. This approach minimizes the risk of cross-contamination between different pharmaceutical products during production. Two sampling techniques are used for surface sampling on the production line: the swab technique and the rinse technique. As established by ICH guidelines, the analytical parameters to be evaluated during method validation include: accuracy, precision (repeatability and intermediate precision), specificity, limit of quantification (LOQ), linearity, range, and robustness. In the context of cleaning method validation, it is also necessary to verify and validate the sampling techniques (swab and/or rinse where applicable). The analytical technique selected for validation is UHPLC (Ultra High Performance Liquid Chromatography) equipped with a CAD detector. This technique allows the separation and quantification of cholesterol residues in the analyzed solutions based on the resulting chromatogram. As reported in the thesis, the results obtained during the validation of the analytical cleaning method meet the acceptance criteria established for all tests performed, in compliance with ICH requirements and the procedure is considered suitable for GMP use in the QC PDS laboratory at Thermo Fisher Scientific, Monza site.| File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.14239/34422