Original article
Guidelines for the practical stability studies of anticancer drugs: A European consensus conferenceRecommandations pour les essais de stabilité pratique des médicaments anticancéreux : une conférence de consensus européenne

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Summary

Stability studies performed by the pharmaceutical industry are only designed to fulfill licensing requirements. Thus, post-dilution or -reconstitution stability data are frequently limited to 24 h only for bacteriological reasons regardless of the true chemical stability which could, in many cases, be longer. In practice, the pharmacy-based centralized preparation may require infusions to be made several days in advance to provide, for example, the filling of ambulatory devices for continuous infusions or batch preparations for dose banding. Furthermore, a non-justified limited stability for expensive products is obviously very costly. Thus, there is a compelling need for additional stability data covering practical uses of anticancer drugs. A European conference consensus was held in France, May 2010, under the auspices of the French Society of Oncology Pharmacy (SFPO) to propose adapted rules on stability in practical situations and guidelines to perform corresponding stability studies. For each anticancer drug, considering their therapeutic index, the pharmacokinetics/pharmacodynamics (PK/PD) variability, specific clinical use and risks related to degradation products, the classical limit of 10% of degradation can be inappropriate. Therefore, acceptance limits must be clinically relevant and should be defined for each drug individually. Design of stability studies has to reflect the different needs of the clinical practice (preparation for the week-ends, outpatient transportations, implantable devices, dose banding…). It is essential to use validated stability-indicating methods, separating degradation products being formed in the practical use of the drug. Sequential temperature designs should be encouraged to replicate problems seen in daily practice such as rupture of the cold-chain or temperature-cycling between refrigerated storage and ambient in-use conditions. Stressed conditions are recommended to evaluate not only the role of classical variables (pH, temperature, light) but also the mechanical stress. Physical stability such as particles’ formation should be systematically evaluated. The consensus conference focused on the need to perform more studies on the stability of biotherapies, including a minimum of three complementary separating methods and a careful evaluation of submicron aggregates. The determination of the biological activity of proteins could be also useful. A guideline on the practical stability of anticancer drugs is proposed to cover current clinical and pharmaceutical practice. It should contribute to improved security of use, optimization of centralized handling and reduced costs. Finally, we have attempted to establish a new drug stability paradigm based on practical clinical needs, to complement regulatory guidelines which are essentially orientated to the stability of manufactured drugs.

Résumé

Les études de stabilité réalisées par l’industrie pharmaceutique sont uniquement orientées sur les exigences de l’autorisation de mise sur le marché. De ce fait, les durées de stabilité postreconstitution ou après dilution sont souvent limitées à 24 heures uniquement pour des raisons bactériologiques sans tenir compte de la stabilité chimique réelle qui peut être beaucoup plus longue. En pratique, les unités centralisées de préparation des chimiothérapies ont besoin de préparer à l’avance pour plusieurs jours, de remplir les dispositifs d’administration ambulatoires ou préparer des lots pour le dose banding. De plus, des données non justifiées de stabilité sont très coûteuses pour des médicaments chers. Il y a donc un besoin urgent de disposer d’études de stabilité sur les anticancéreux qui couvrent les pratiques quotidiennes. Une conférence de consensus européenne s’est tenue en France en mai 2010, sous les auspices de la Société française de pharmacie oncologique (SFPO) pour proposer des règles adaptées de stabilité et des recommandations pour réaliser les essais afférents. Pour chaque anticancéreux, en considérant son index thérapeutique, la variabilité pharmacocinétique/pharmacodynamie, ses utilisations cliniques spécifiques et les risques liés aux produits de dégradation, la limite classique de 10 % maximum de dégradation peut être inappropriée. De ce fait, les limites d’acceptation doivent être cliniquement justifiées et définies médicament par médicament. Le design des études de stabilité doit refléter les différents besoins de la pratique clinique (préparation pour un week-end, transport pour patients externes, chambres implantables, dose banding). Il est essentiel d’employer des méthodes indicatrices de stabilité validées séparant les produits de dégradation. Les études séquentielles de température devraient être encouragées pour mimer les problèmes pouvant intervenir en pratique quotidienne comme les ruptures de chaîne du froid. Les conditions stressées sont recommandées pour évaluer non seulement les paramètres classiques (température, lumière…) mais aussi les stress mécaniques. La stabilité physique (formation de microparticules) doit être systématiquement recherchée. La conférence de consensus s’est focalisée sur le besoin de promouvoir les études de stabilité sur les biothérapies qui doivent inclure au moins trois méthodes séparatives complémentaires et évaluer la formation de micro-agrégats. La détermination de l’activité biologique peut être intéressante. Des recommandations sur la stabilité pratique des anticancéreux ont été proposées pour couvrir les besoins actuels, tant cliniques que pharmaceutiques. Elles devraient contribuer à améliorer leur sécurité d’emploi, optimiser le fonctionnement des unités de reconstitution et réduire les coûts. In fine, nous proposons d’établir un nouveau paradigme sur la stabilité des médicaments et les études afférentes qui tienne plus compte des besoins en pratique et complémentaire des exigences réglementaires essentiellement orientées sur les demandes d’enregistrement.

Section snippets

Background

Stability studies performed by the pharmaceutical industry are only designed to fulfill licensing requirements. When medicines are being licensed, little attention is given to the practical use of these drugs and there is no recognition that pharmaceuticals start a new life once they are prepared for patient administration. When reviewing package inserts, the general assumption is that a drug will be reconstituted, if necessary, and administered on a clinical ward. But increasingly the

Methods

A European conference consensus was held in France, Abbaye des Vaux de Cernay, May 2010, under the auspices of the French Society of Oncology Pharmacy (SFPO) to define adapted rules on stability in practical situations and to propose guidelines to perform the corresponding stability studies. A panel of ten European experts shared their specific and “practical” experience and worked during two days to produce guidelines. This panel is referred as “consensus group”. Conference consensus was

Unresolved questions

After examination of the literature, the initial postulate was that many unresolved questions remained, such as:

  • The relevant stability limits for practical purposes, including the question of those for degradation products.

  • The kind of methods to be used when ICH guidelines are non adapted both for physical and chemical evaluation.

  • The evolutions of protocols of stressed conditions.

  • The need of more relevant design for stability studies (i.e. sequential cycling and non isothermal studies).

  • The

Conclusion

All of the drugs used in modern medicine are licensed with very limited stability data which are insufficient to fulfil the new ways of drugs being handled in the 21st century clinical environment. As a consequence, there is an urgent need for additional data to support the pharmaceutical quality of these practices. Ideally, the drug development programs of pharmaceutical industry should generate enough stability data to allow for a more flexible clinical application, or would make available to

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.

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    This article presents the outcomes from the SFPO First European workshop on methodology in drug stability studies in the field of oncology, 14–15 May, 2010, Abbaye-des-Vaux-de-Cernay, France.

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