This thesis project has been carried out in the Novartis Pharmanalytica Analytical Science & Technology department, Locarno (CH). Core business of Pharmanalytica are the stability studies on Novartis finished pharmaceutical products. The AS&T team is specialized in the activities of analytical method development, validation and transfer; besides, the team fulfils other enquiries coming from pharmaceutical regulatory institutions or authorities. The objective of this project has been to develop, validate and apply analytical HPLC-UV procedures aimed at: • Assessing the in-use stability of the drug product Sandimmun® concentrate solution for infusion 50mg/1mL • Determining the amount of bis (2-ethylhexyl) phthalate DEHP leaching from the parenteral administration devices and administered to the patient undergoing therapy with Sandimmun®. DEHP is the most used plasticizer in the manufacturing of PVC parenteral administration devices. DEHP is considered to be harmful to the human health. The work stems from Novartis’ need to align the requirements of the Public Health Institute of Chile which has established, through a new law effective since April 2015, new guidelines for the registration of injectable pharmaceutical products. These new requirements include the need to specify data relating to the in-use stability for these products, that is the time period during which the product maintain his quality, efficacy and safety characteristics when it has been removed from its original packaging and it is at the conditions of use as stated by the manufacturer. Sandimmun® injectable is marketed in Chile, the company is therefore required to conform to these new guidelines presenting data on its in-use stability. The evaluation of the in-use stability of Sandimmun® include the determination of the amount of DEHP leaching from the plastic of the devices for parenteral administration and taken by the patient undergoing therapy with Sandimmun®. After concluding the development and validation of methods, these have been used for the in-use stability study of Sandimmun®. The developed methods are three: 1. Assay 2. Determination of the degradation products 3. Determination of the DEHP After an initial literature search about the product and the chemical-physical characteristics of Cyclosporine and its known degradation products, the experimental part of the development of the methods has been conducted. During the work a large number of tests have been performed in order to understand the chromatographic behaviour of the active ingredient, the impurities and the excipients in the formulation. For the determination of the degradation products the tests have led to the identification of a gradient chromatography which allows the separation of Cyclosporine, its degradation products and the interfering chromatographic peaks generated from the excipients present in the finished product. The method for the assay was a simplification of the method for the determination of the degradation products. In this case, the obstacles encountered during the method development for the degradants were overcome through a simple dilution step, given the higher concentration of cyclosporine for the assay. The method for the determination of DEHP was developed by a second analyst belonging to the AS&T team. It was also necessary to develop an algorithm that allowed the interpretation of DEHP concentration values found in bag, in order to convert them into the amount administered to the patient undergoing therapy with Sandimmun®. After the development, the methods have been subjected to the process of validation according to ICH guidelines, through which it has been demonstrated that they are suitable for the analytical purposes they were intended for. The final methods were then applied to the actual analysis for the in-use stability study of Sandimmun® at its conditions of use.
Il lavoro di tesi è stato eseguito presso il dipartimento di Analytical Science & Technology group (AS&T) di Novartis Pharmanalytica, Locarno (CH). Il core business di Pharmanalytica sono gli studi di stabilità sul prodotto finito. Il gruppo AS&T si occupa principalmente delle attività di sviluppo, convalida e trasferimento di metodi analitici, oltre che delle altre richieste provenienti da enti regolatori e autorità del settore. Lo scopo del lavoro è stato sviluppare, convalidare e applicare metodi HPLC-UV al fine di: • Valutare la in-use stability del prodotto finito Sandimmun® iniettabile 50mg/1mL • Determinare la quantità di DEHP estratta dai dispositivi per somministrazione parenterale e somministrata al paziente in terapia con Sandimmun®. Il DEHP è un plasticizzante potenzialmente tossico per la salute dell’uomo, utilizzato nella produzione di dispositivi medici, quali contenitori in PVC per soluzioni parenterali. Il lavoro nasce dall’esigenza di Novartis di allinearsi alle richieste dell’Istituto di Sanità Pubblica del Cile, il quale ha stabilito, attraverso una nuova legge in vigore dall’Aprile 2015, delle nuove linee guida per la registrazione dei prodotti farmaceutici iniettabili. Queste richieste includono la necessità di specificare dati inerenti alla in-use stability per tali prodotti, ovvero il periodo di tempo durante il quale il farmaco mantiene le sue caratteristiche di qualità, efficacia e sicurezza, allorquando sia stato rimosso dal suo confezionamento originario e si trovi alle condizioni di utilizzo dichiarate dal produttore. Sandimmun® iniettabile è tra i prodotti Novartis commercializzati in Cile, l’azienda è dunque tenuta ad allinearsi a tali richieste presentando dati riguardanti la sua in-use stability. La valutazione della stabilità di Sandimmun® alle sue condizioni di utilizzo comprende la determinazione della quantità di DEHP estratto dalle plastiche dei dispositivi per somministrazione parenterale e quindi assunto dal paziente in terapia con Sandimmun®. Una volta conclusi lo sviluppo e la convalida dei metodi, questi sono stati utilizzati per lo studio di in-use stability di Sandimmun®. I metodi sviluppati sono tre: 1. Assay 2. Determinazione dei prodotti di degradazione 3. Determinazione del contenuto di DEHP Dopo un’iniziale ricerca bibliografica sul prodotto e sulle caratteristiche chimico-fisiche della Ciclosporina e dei suoi prodotti di degradazione, è stata condotta la parte sperimentale di sviluppo dei metodi. Il lavoro ha previsto numerosi test volti a comprendere il comportamento cromatografico del principio attivo, delle impurezze e degli eccipienti presenti nella formulazione. I test hanno portato all’identificazione, per la determinazione dei prodotti di degradazione, di un metodo cromatografico in gradiente che permette la separazione di tutti gli analiti presenti nel prodotto finito. Il metodo per l’assay è risultato essere una semplificazione del metodo per la determinazione dei prodotti di degradazione. In questo caso gli ostacoli incontrati durante lo sviluppo del metodo per i degradati sono stati superati attraverso un semplice passaggio di diluizione, possibile grazie alle maggiori concentrazioni di lavoro per l’assay. Il metodo per la determinazione del DEHP è stato sviluppato parallelamente da un secondo analista del team AS&T. È stato inoltre necessario sviluppare un algoritmo che permettesse di interpretare i valori di concentrazione in sacca ottenuti per il DEHP al fine di convertirli in quantità assunte dal paziente durante la terapia con Sandimmun®. In seguito alle fasi di sviluppo i metodi sono stati sottoposti al processo di convalida secondo le linee guida ICH, attraverso il quale è stato dimostrato che essi sono idonei agli scopi analitici per cui sono stati sviluppati. I metodi definitivi sono quindi stati applicati allo studio di in-use stability di Sandimmun®.
Sviluppo di metodi HPLC-UV per la valutazione della stabilità di Sandimmun® alle sue condizioni di utilizzo
DI MARIA, FRANCESCO
2015/2016
Abstract
This thesis project has been carried out in the Novartis Pharmanalytica Analytical Science & Technology department, Locarno (CH). Core business of Pharmanalytica are the stability studies on Novartis finished pharmaceutical products. The AS&T team is specialized in the activities of analytical method development, validation and transfer; besides, the team fulfils other enquiries coming from pharmaceutical regulatory institutions or authorities. The objective of this project has been to develop, validate and apply analytical HPLC-UV procedures aimed at: • Assessing the in-use stability of the drug product Sandimmun® concentrate solution for infusion 50mg/1mL • Determining the amount of bis (2-ethylhexyl) phthalate DEHP leaching from the parenteral administration devices and administered to the patient undergoing therapy with Sandimmun®. DEHP is the most used plasticizer in the manufacturing of PVC parenteral administration devices. DEHP is considered to be harmful to the human health. The work stems from Novartis’ need to align the requirements of the Public Health Institute of Chile which has established, through a new law effective since April 2015, new guidelines for the registration of injectable pharmaceutical products. These new requirements include the need to specify data relating to the in-use stability for these products, that is the time period during which the product maintain his quality, efficacy and safety characteristics when it has been removed from its original packaging and it is at the conditions of use as stated by the manufacturer. Sandimmun® injectable is marketed in Chile, the company is therefore required to conform to these new guidelines presenting data on its in-use stability. The evaluation of the in-use stability of Sandimmun® include the determination of the amount of DEHP leaching from the plastic of the devices for parenteral administration and taken by the patient undergoing therapy with Sandimmun®. After concluding the development and validation of methods, these have been used for the in-use stability study of Sandimmun®. The developed methods are three: 1. Assay 2. Determination of the degradation products 3. Determination of the DEHP After an initial literature search about the product and the chemical-physical characteristics of Cyclosporine and its known degradation products, the experimental part of the development of the methods has been conducted. During the work a large number of tests have been performed in order to understand the chromatographic behaviour of the active ingredient, the impurities and the excipients in the formulation. For the determination of the degradation products the tests have led to the identification of a gradient chromatography which allows the separation of Cyclosporine, its degradation products and the interfering chromatographic peaks generated from the excipients present in the finished product. The method for the assay was a simplification of the method for the determination of the degradation products. In this case, the obstacles encountered during the method development for the degradants were overcome through a simple dilution step, given the higher concentration of cyclosporine for the assay. The method for the determination of DEHP was developed by a second analyst belonging to the AS&T team. It was also necessary to develop an algorithm that allowed the interpretation of DEHP concentration values found in bag, in order to convert them into the amount administered to the patient undergoing therapy with Sandimmun®. After the development, the methods have been subjected to the process of validation according to ICH guidelines, through which it has been demonstrated that they are suitable for the analytical purposes they were intended for. The final methods were then applied to the actual analysis for the in-use stability study of Sandimmun® at its conditions of use.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/21479