Abstract. This summary workshop report highlights presentations and over-arching themes from an October 2011 workshop. Discussions focused on best practices in the application of biopharmaceutics in oral drug product development and evolving bioequivalence approaches. Best practices leverage biopharmaceutic data and other drug, formulation, and patient/disease data to identify drug development challenges in yielding a successfully performing product. Quality by design and product developability paradigms were discussed. Development tools include early development strategies to identify critical absorption factors and oral absorption modeling. An ongoing theme was the desire to comprehensively and systematically assess risk of product failure via the quality target product profile and root cause and risk analysis. However, a parallel need is reduced timelines and fewer resources. Several presentations discussed applying Biopharmaceutics Classification System (BCS) and in vitro-in vivo correlations in development and in post-development and discussed both resource savings and best scientific practices. The workshop also focused on evolving bioequivalence approaches, with emphasis on highly variable products (HVDP), as well as specialized modified-release products. In USA, two bioequivalence approaches for HVDP are the reference-scaled average bioequivalence approach and the two-stage group-sequential design. An adaptive sequential design approach is also acceptable in Canada. In European Union, two approaches for HVDP are a two-stage design and an approach to widen C max acceptance limits. For some specialized modified-release products, FDA now requests partial area under the curve. Rationale and limitations of such metrics were discussed (e.g., zolpidem and methylphenidate). A common theme was the benefit of the scientific and regulatory community developing, validating, and harmonizing newer bioequivalence methodologies (e.g., BCS-based waivers and HVDP trial designs).
The objective of the current work was to study an observed incompatibility between croscarmellose sodium and basic excipients in a tablet formulation. Significant dissolution slowdown was observed for alkaline tablet compositions of an acid-labile drug containing croscarmellose sodium (CCS) as a disintegrant. The severity of the dissolution slowdown was directly proportional to both the degree of alkalinity and the level of CCS in the tablet formulation. It is postulated that the ester cross-links in CCS were partially or fully hydrolyzed under basic conditions (pH values >9) forming by-products of increased water solubility. This increase in the level of water-soluble polymer can lead to the formation of a viscous barrier in the tablet upon moisture uptake, thus slowing down its dissolution. The dissolution slowdown was not observed for a similar alkaline tablet preparation containing crospovidone as a disintegrant.
Chimeric BR96-doxorubicin conjugate (BR96-DOX) is an immunoconjugate designed to specifically target and kill certain tumor cells. The linker between the chimeric BR96 antibody and DOX is an acid-labile hydrazone group which was designed to undergo lysosomal hydrolysis to release DOX in vivo. Stability studies indicated that acid-catalyzed hydrazone hydrolysis was the major degradation route in vitro. Even under optimal conditions of pH and temperature, the stability of BR96-DOX in solution was not acceptable for long-term storage. Lyophilization of BR96-DOX in the presence of added sugars, such as lactose or sucrose, and subsequent storage of the lyophile under refrigeration significantly improved the stability. Therefore lyophilization appears to be a viable approach for achieving long-term stabilization of BR96-DOX.
A proposed mechanism of spherical particle formation of the 3:1 zinc peptide encompasses the freezing of a TBA/water solution (20-70% TBA) causing the formation of a TBA hydrate phase ("dispersed TBA hydrate"). Decreasing the temperature further causes the formation of a eutectic mixture between TBA hydrate ("eutectic TBA hydrate") and water. Due to its low aqueous solubility, the zinc peptide adduct accumulates in both of the dispersed and eutectic TBA hydrate phases to form a hydrophobic "oil" phase. Since the eutectic TBA hydrate phase is surrounded by ice, a "solid emulsion" forms to lower the interfacial energy, and gives rise to spherical zinc peptide particles upon solvent sublimation. Possibility of liquid-liquid phase separation during freeze-drying was also investigated, and no evidence was found to support this alternative mechanism.
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