The quality of a medicinal product depends not only on the active ingredient and excipients, but on the entire system surrounding it: manufacturing processes, packaging materials, delivery devices, and storage conditions. The introduction of polymers, complex coatings, and new materials has shown that packaging is not a passive element, but a potential source of chemical contamination. From this awareness arises the discipline of Extractables & Leachables, now central to the assessment of material–product compatibility. Impurities originating from packaging include residual monomers, additives, plasticizers, oligomers, degradation products, and NIAS (Non-Intentionally Added Substances). Unlike organic, inorganic, or degradation impurities, they do not depend on the drug itself but on the material. Their migration into the medicinal product may alter its stability, modify its toxicological profile, or cause adverse effects. For this reason, regulatory authorities have expanded the framework of guidelines (ICH Q3A–Q3D, M7) up to the recent ICH Q3E draft, specifically dedicated to Extractables & Leachables. The modern approach is risk-based: the criticality of a compound depends on its concentration, exposure, and intrinsic hazard. Tools such as Permitted Daily Exposure, Threshold of Toxicological Concern, and Analytical Evaluation Threshold allow analytical and toxicological data to be integrated into a coherent decision making framework. In particular, the AET defines the analytical threshold above which a detected peak must be identified and evaluated. The work described in this thesis was carried out at LabAnalysis, Casanova Lonati (PV). Case Study 1 – Hydrophilic cream in aluminum tubes with epoxy coating The phenolic epoxy coating may release melamine, BADGE and its chlorinated derivatives, as well as traces of Bisphenol A. The complexity of the semisolid matrix required an in depth study of sample dilutions (1:10–1:2000) to reduce matrix effects. LC-MS methods were developed in ESI+ (melamine) and ESI− (BADGE-HCl, BADGE-2HCl, Bisphenol A). Application to real samples revealed the presence of BADGE derivatives and traces of melamine, at concentrations below toxicological limits but relevant for compatibility assessment. Case Study 2 – Simulated migration using a hydroalcoholic solution The real formulation was too complex for direct analysis, so a hydroalcoholic simulant was used. BADGE, Bisphenol A, chlorinated derivatives, melamine, and semi volatile compounds were investigated. LC-MS and GC-MS methods were adapted to the new matrix. The simulant faithfully reproduced the behavior of the real formulation, confirming the presence of BADGE-HCl, BADGE-2HCl, and traces of Bisphenol A, consistent with the extractables study. Summary of results: The two case studies show that the evaluation of leachables requires a multidisciplinary approach combining analytical chemistry, toxicology, and material science. The analytical strategy depends on the matrix, packaging, expected analytes, and regulatory requirements. The combined use of LC-MS and GC-MS allows coverage of a wide range of compounds. The AET guides the identification of truly critical peaks, while toxicological assessment determines whether the observed migration represents a risk. Conclusions: The management of Extractables & Leachables is now an essential component of modern pharmaceutical quality. Robust analytical methods, risk based thresholds, and the integration of chemical and toxicological data ensure patient safety and packaging–product compatibility. The two case studies provide a model applicable to future E&L evaluations, contributing to the understanding of interactions between packaging materials and pharmaceutical formulations.
La qualità di un medicinale dipende non solo dal principio attivo e dagli eccipienti, ma dall’intero sistema che lo circonda: processi produttivi, materiali di confezionamento, dispositivi di somministrazione e condizioni di conservazione. L’introduzione di polimeri, rivestimenti complessi e nuovi materiali ha mostrato che il packaging non è un elemento passivo, ma una possibile fonte di contaminazione chimica. Da questa consapevolezza nasce la disciplina degli Extractables & Leachables, oggi centrale nella valutazione della compatibilità tra materiale e prodotto. Le impurezze derivanti dal packaging includono monomeri residui, additivi, plastificanti, oligomeri, prodotti di degradazione e NIAS (Non Intentionally Added Substances). A differenza delle impurezze organiche, inorganiche o di degradazione, non dipendono dal farmaco ma dal materiale stesso. La loro migrazione può alterare la stabilità del medicinale, modificarne il profilo tossicologico o generare effetti avversi. Per questo, le autorità regolatorie hanno ampliato il quadro normativo (ICH Q3A–Q3D, M7) fino al recente draft ICH Q3E, dedicato specificamente agli Extractables & Leachables. L’approccio moderno è basato sul rischio: la criticità di un composto dipende da concentrazione, esposizione e pericolosità. Strumenti come Permitted Daily Exposure, Threshold of Toxicological Concern e Analytical Evaluation Threshold permettono di integrare dati analitici e tossicologici. In particolare, l’AET definisce la soglia oltre la quale un picco deve essere identificato e valutato. Il lavoro descritto in questa tesi è stato svolto presso LabAnalysis, Casanova Lonati (PV). Caso Studio 1 – Crema idrofila in tubi di alluminio con coating epossidico Il rivestimento fenolico epossidico può rilasciare melamina, BADGE e derivati clorurati, oltre a tracce di Bisphenol A. La complessità della matrice semisolida ha richiesto uno studio approfondito delle diluizioni (1:10–1:2000) per ridurre l’effetto matrice. Sono state sviluppate metodiche LC-MS in ESI+ (melamina) ed ESI− (BADGE-HCl, BADGE-2HCl, Bisphenol A). L’applicazione ai campioni reali ha evidenziato la presenza di derivati del BADGE e tracce di melamina, in concentrazioni inferiori ai limiti tossicologici ma rilevanti per la compatibilità. Caso Studio 2 – Migrazione simulata con soluzione idroalcolica La formulazione reale era troppo complessa per l’analisi diretta, quindi è stato impiegato un simulante idroalcolico. Sono stati investigati BADGE, Bisphenol A, derivati clorurati, melamina e composti semi volatili. Le metodiche LC-MS e GC-MS sono state adattate alla nuova matrice. Il simulante ha riprodotto fedelmente il comportamento della formulazione reale, confermando la presenza di BADGE HCl, BADGE 2HCl e tracce di Bisphenol A, coerenti con lo studio di extractables. Sintesi dei risultati: I due casi studio mostrano che la valutazione dei leachables richiede un approccio multidisciplinare che combini chimica analitica, tossicologia e conoscenza dei materiali. La scelta della strategia dipende dalla matrice, dal packaging e dagli analiti attesi. L’uso combinato di LC-MS e GC-MS permette di coprire un ampio spettro di composti. L’AET guida l’identificazione dei picchi realmente critici, mentre la valutazione tossicologica stabilisce se la migrazione osservata rappresenti un rischio. Conclusioni: La gestione degli Extractables & Leachables è oggi una componente essenziale della qualità farmaceutica. Metodiche analitiche robuste, soglie basate sul rischio e integrazione tra dati chimici e tossicologici consentono di garantire sicurezza e compatibilità packaging–prodotto. I due casi studio forniscono un modello applicabile a future valutazioni Extractables & Leachables, contribuendo alla comprensione delle interazioni tra materiali di confezionamento e formulazioni farmaceutiche.
Extractables & Leachables nei sistemi di confezionamento farmaceutico: sviluppo di metodiche analitiche per l’identificazione e la caratterizzazione dei Leachables nei medicinali ad uso umano
LIVRAGHI, ARIANNA
2025/2026
Abstract
The quality of a medicinal product depends not only on the active ingredient and excipients, but on the entire system surrounding it: manufacturing processes, packaging materials, delivery devices, and storage conditions. The introduction of polymers, complex coatings, and new materials has shown that packaging is not a passive element, but a potential source of chemical contamination. From this awareness arises the discipline of Extractables & Leachables, now central to the assessment of material–product compatibility. Impurities originating from packaging include residual monomers, additives, plasticizers, oligomers, degradation products, and NIAS (Non-Intentionally Added Substances). Unlike organic, inorganic, or degradation impurities, they do not depend on the drug itself but on the material. Their migration into the medicinal product may alter its stability, modify its toxicological profile, or cause adverse effects. For this reason, regulatory authorities have expanded the framework of guidelines (ICH Q3A–Q3D, M7) up to the recent ICH Q3E draft, specifically dedicated to Extractables & Leachables. The modern approach is risk-based: the criticality of a compound depends on its concentration, exposure, and intrinsic hazard. Tools such as Permitted Daily Exposure, Threshold of Toxicological Concern, and Analytical Evaluation Threshold allow analytical and toxicological data to be integrated into a coherent decision making framework. In particular, the AET defines the analytical threshold above which a detected peak must be identified and evaluated. The work described in this thesis was carried out at LabAnalysis, Casanova Lonati (PV). Case Study 1 – Hydrophilic cream in aluminum tubes with epoxy coating The phenolic epoxy coating may release melamine, BADGE and its chlorinated derivatives, as well as traces of Bisphenol A. The complexity of the semisolid matrix required an in depth study of sample dilutions (1:10–1:2000) to reduce matrix effects. LC-MS methods were developed in ESI+ (melamine) and ESI− (BADGE-HCl, BADGE-2HCl, Bisphenol A). Application to real samples revealed the presence of BADGE derivatives and traces of melamine, at concentrations below toxicological limits but relevant for compatibility assessment. Case Study 2 – Simulated migration using a hydroalcoholic solution The real formulation was too complex for direct analysis, so a hydroalcoholic simulant was used. BADGE, Bisphenol A, chlorinated derivatives, melamine, and semi volatile compounds were investigated. LC-MS and GC-MS methods were adapted to the new matrix. The simulant faithfully reproduced the behavior of the real formulation, confirming the presence of BADGE-HCl, BADGE-2HCl, and traces of Bisphenol A, consistent with the extractables study. Summary of results: The two case studies show that the evaluation of leachables requires a multidisciplinary approach combining analytical chemistry, toxicology, and material science. The analytical strategy depends on the matrix, packaging, expected analytes, and regulatory requirements. The combined use of LC-MS and GC-MS allows coverage of a wide range of compounds. The AET guides the identification of truly critical peaks, while toxicological assessment determines whether the observed migration represents a risk. Conclusions: The management of Extractables & Leachables is now an essential component of modern pharmaceutical quality. Robust analytical methods, risk based thresholds, and the integration of chemical and toxicological data ensure patient safety and packaging–product compatibility. The two case studies provide a model applicable to future E&L evaluations, contributing to the understanding of interactions between packaging materials and pharmaceutical formulations.| File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.14239/36508