To ensure the highest level of quality and minimize any risk to patient safety, any facility where active pharmaceutical ingredients (APIs) are manufactured needs to be run according to strict adherence to cGMP (current Good Manufacturing Practices) requirements, so that the APIs are free from contamination. In recent years, the requirements placed by the pharmaceutical authorities on the manufacturers of pharmaceutical products have increased enormously. In the course of this, special attention is paid to the production facilities in which several different pharmaceutical products are manufactured (so-called multi-purpose facilities). In order to avoid contamination of the products in multi-purpose facilities, the cleaning of the production plants according to validated procedures is required. The documented proof must be provided that a corresponding cleaning process of the production plants is effective in the long term and that the required degree of cleaning is achieved. For the type of multipurpose facility where multiple products and their intermediates are synthesized in the same vessels and equipment, the cleaning requirements are significantly high. To prevent cross-contamination, one of the first activities that is undertaken is to establish an effective cleaning methodology and this is the result of the work of a multi-disciplinary team including Chemical development, Production, Quality Assurance and Quality Control. The chemical development group should make a qualitative assessment of the target compound’s solubility in a number of different solvents, and this solubility data can be used to aid the development of both an equipment cleaning procedure and to define a rinse for the cleaning verification analytical method. It is then important that analytical methods are in place in advance because it is not possible to demonstrate cleanliness after the campaign without them. The goal of a clean-out method is to ensure that the material evaluated is accurately quantitated in order to ensure cleanliness of the equipment. Clean-out methods are typically developed for both rinse and swab samples. Analytical methods for cleaning check need to be validated. Method validation activities are necessary every time a new product is introduced in the facility or when a change to an established manufacturing process (i.e. introduction of a new equipment) or to cleaning conditions is done. From the knowledge of the manufacturing process and of the cleaning conditions, it is possible to identify the potential residues to be analyzed and then to determine the most appropriate analytical technique to be used to determine their relevant concentration levels. Specific analytical techniques are preferred but non-specific ones are also accepted; the key element in its selection is that the technique provides a result that has a logical, scientific link with the residue. The purpose of this experimental thesis was to develop and validate an analytical method suitable for the determination and quantification of two residues (named “residue A” and “residue B”), that could remain in the final rinse and onto the inner surface of the equipment used for the manufacturing of an Active Pharmaceutical Ingredient (API) intermediate. This API is currently under clinical development for inflammatory indications and covered by label. Both residues A and B have a chromophore group into their structures. Therefore, it was decided to develop a HPLC method to determine their concentration into rinse and swab samples. Analytical validation was performed as described into ICH.
Il processo di pulizia, in un impianto di un’azienda chimico-farmaceutica, ha un ruolo fondamentale soprattutto per impianti multi-purpose, ovvero per impianti non dedicati ad una specifica produzione e che possono essere impiegati, in momenti diversi, per la produzione di differenti intermedi e principi attivi. La pulizia viene effettuata per evitare fenomeni di contaminazione crociata (cross-contamination), ovvero che residui del prodotto precedente contaminino il prodotto successivo a di sopra di un valore considerato pericoloso per il paziente che assumerà il farmaco contenente un certo principio attivo. La pulizia delle apparecchiature garantisce, quindi, la qualità di un farmaco e la sicurezza del paziente. I processi di pulizia e i metodi che ne verificano l’efficacia devono essere convalidati per dimostrarne la specificità, la riproducibilità, la precisione e la robustezza. A livello organizzativo, le procedure di pulizia delle apparecchiature vengono definite da diversi reparti (produzione, ricerca e sviluppo, laboratorio controllo qualità, ingegneria e assicurazione qualità). Lo scopo di questo lavoro è quello di sviluppare e validare un metodo analitico adatto alla determinazione e quantificazione di due specie chimiche (residui nelle apparecchiature dopo la pulizia) relative al primo step di sintesi nella produzione di un principio attivo (API), in fase di sviluppo clinico per indicazioni infiammatorie. Questo lavoro prende in considerazione i compiti svolti dal laboratorio controllo qualità e nello specifico: vengono eseguite le cinetiche degradazione dei residui in un set di potenziali agenti di lavaggio, selezionati in base alla solubilità delle specie negli stessi. Queste prove sono finalizzate all’individuazione dell’agente di lavaggio e delle migliori condizioni di bonifica in impianto; viene sviluppato un metodo HPLC per la determinazione e quantificazione dei residui dell’intermedio farmaceutico, potenzialmente presenti sulla superficie interna delle apparecchiature al termine della bonifica. Per questa attività, si tiene conto dei limiti di concentrazione calcolati partendo dal massimo residuo permissibile, determinato in base ai dati di tossicità dei residui da ricercare (PDE o LD50); viene validato il metodo sviluppato secondo quanto richiesto da cGMP e dalle linee guida di riferimento (ICH). I due residui (residuo A e residuo B) considerati sono rispettivamente la materia prima e il prodotto di reazione del primo passaggio sintetico per la produzione del principio attivo sopra descritto. Lo sviluppo e la convalida del metodo prenderanno in considerazione le due tipologie di campione che, a seguito del processo di pulizia dell’impianto, sono analizzati dal laboratorio controllo qualità: i campioni di risciacquo (rinse), costituiti da un’aliquota dall’agente di lavaggio, prelevato al termine della bonifica del treno di apparecchiature; i campioni di swab, costituiti da filtri in cellulosa che, a seguito dello sfregamento sulla superficie di un’apparecchiatura, tratterranno i eventuali residui di prodotto, che verranno estratti in laboratorio con un opportuno solvente.
Sviluppo e convalida di un metodo analitico per la determinazione dei residui di pulizia in un impianto produttivo multipurpose
BETTANI, DARIO
2019/2020
Abstract
To ensure the highest level of quality and minimize any risk to patient safety, any facility where active pharmaceutical ingredients (APIs) are manufactured needs to be run according to strict adherence to cGMP (current Good Manufacturing Practices) requirements, so that the APIs are free from contamination. In recent years, the requirements placed by the pharmaceutical authorities on the manufacturers of pharmaceutical products have increased enormously. In the course of this, special attention is paid to the production facilities in which several different pharmaceutical products are manufactured (so-called multi-purpose facilities). In order to avoid contamination of the products in multi-purpose facilities, the cleaning of the production plants according to validated procedures is required. The documented proof must be provided that a corresponding cleaning process of the production plants is effective in the long term and that the required degree of cleaning is achieved. For the type of multipurpose facility where multiple products and their intermediates are synthesized in the same vessels and equipment, the cleaning requirements are significantly high. To prevent cross-contamination, one of the first activities that is undertaken is to establish an effective cleaning methodology and this is the result of the work of a multi-disciplinary team including Chemical development, Production, Quality Assurance and Quality Control. The chemical development group should make a qualitative assessment of the target compound’s solubility in a number of different solvents, and this solubility data can be used to aid the development of both an equipment cleaning procedure and to define a rinse for the cleaning verification analytical method. It is then important that analytical methods are in place in advance because it is not possible to demonstrate cleanliness after the campaign without them. The goal of a clean-out method is to ensure that the material evaluated is accurately quantitated in order to ensure cleanliness of the equipment. Clean-out methods are typically developed for both rinse and swab samples. Analytical methods for cleaning check need to be validated. Method validation activities are necessary every time a new product is introduced in the facility or when a change to an established manufacturing process (i.e. introduction of a new equipment) or to cleaning conditions is done. From the knowledge of the manufacturing process and of the cleaning conditions, it is possible to identify the potential residues to be analyzed and then to determine the most appropriate analytical technique to be used to determine their relevant concentration levels. Specific analytical techniques are preferred but non-specific ones are also accepted; the key element in its selection is that the technique provides a result that has a logical, scientific link with the residue. The purpose of this experimental thesis was to develop and validate an analytical method suitable for the determination and quantification of two residues (named “residue A” and “residue B”), that could remain in the final rinse and onto the inner surface of the equipment used for the manufacturing of an Active Pharmaceutical Ingredient (API) intermediate. This API is currently under clinical development for inflammatory indications and covered by label. Both residues A and B have a chromophore group into their structures. Therefore, it was decided to develop a HPLC method to determine their concentration into rinse and swab samples. Analytical validation was performed as described into ICH.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.
Per maggiori informazioni e per verifiche sull'eventuale disponibilità del file scrivere a: unitesi@unipv.it.
https://hdl.handle.net/20.500.14239/12405