The Relations Between Q3 Measurements, In vitro Release and TCS

Abstract

The Topical drug Classification System (TCS) is a framework specifically design for the comparative assessment of semisolid dosage forms. Compared to the Biopharmaceutics Classification System, TCS relies on the assessment of the qualitative and quantitative compositions as well as on the sensitivity of the in vitro release tests (IVRT) to signal potential differences in the microstructure. The arrangement of the components of the semisolid matrix is the complex results of the nature and intensity of interactions between the excipients, the impact of the manufacturing process and the changes which occurring during the shelf life of the product. When applied in vivo, a topical dosage form is subjected to shearing forces for spreading at the site of administration. The complexity of structural changes is difficult to simulate in vitro and a wide variety of methods have been proposed to evaluate the internal interactions for a cream, gel or ointment. For the comparative assessment of topical semisolids, the available guidance documents have strict requirements in terms of similarity of the qualitative and quantitative composition (Q1 and Q2). Differences in the amounts of the same excipients are usually limited to +/-5%, considering their potential role in the permeation and penetration across the skin barrier. Larger limits, i.e. +/10% are mentioned ingredients with specific functionality by the current version of the European Medicine Agency draft guidance on quality and equivalence of topical products. For mitigation of the risks associated with the manufacturing process, several rheological parameters are to be evaluated, i.e. yield stress, storage and loss modulus, zero-shear viscosities or areas and model parameters associated with the thixotropy loops. Considering the product-specific draft guidance issued by US-Food and Drug Administration (US-FDA), the assessment of Q3 (microstructural) similarity depends upon the complexity of the dosage forms and may include, in addition to rheology, specific parameters, such as particle or droplet size determination, crystal behavior, polymorphism, fraction of drug dissolved etc. IVRT was initially mentioned in the SUPAC-SS guidance of US-FDA (1997) for the evaluation of well defined, level 2 changes of composition or manufacturing process, based on the ability to reflect in aggregate the influence of several critical variables. Gradually, its role and applicability have been extended to comparison of topical semisolid across manufacturers. In the 1998 draft guidance Topical dermatological drug product NDA’s and ANDA’s In vivo bioavailability, bioequivalence, in vitro release, and associated studies, IVRT was proposed for the evaluation of the lower strength, once the bioequivalence for the higher strength of a generic product has been demonstrated in relation with the reference. Moreover, as part of “sponsor-specific comparability protocol”, IVRT was to be used for approval of more extensive variations, beyond SUPAC-SS level 2. Even though this part was never contested, it was withdrawn together with the dermato-pharmacokinetics methodology in 2002. Currently, the EMA draft guidance (2018) assigns a central role to IVRT, as it is “required to support” the new concept of extended pharmaceutical equivalence. An additional level of similarity has been mentioned, considering the impact of methods and means of administration (Q4). The device may alter the microstructure of the semisolid before the application, therefore test conditions mimicking the in vivo use are essential for adequate comparison. The term history of formulation includes transformation occurring beyond the manufacturing process. The creams, gels and ointments are subject to time, shear and temperature dependent modification of the arrangement of the matter, which may alter their quality and performance. PL-21 The Relations Between Q3 Measurements, In vitro Release and TCS