Science- and Risk-Based Stability Strategies to Support Product Lifecycle Changes.

ICH Q12 asserts that science- and risk-based approaches are applicable to stability studies supporting Chemistry, Manufacturing and Controls (CMC) post-approval changes (PAC) to enable more timely implementation; however, no guidance or specific examples are provided to demonstrate how prior knowledge of the product can inform the risk assessment for the proposed change(s). Ten diverse case studies are presented in this manuscript to demonstrate how science- and risk-based stability strategies were used to support drug substance and product CMC PAC and lifecycle management activities. The accumulated stability knowledge held by original manufacturers of marketed products is substantial, and different elements of this knowledge base were used to assess the risks and impact of the proposed changes for confident change management. This paper provides ways to leverage science- and risk-based stability strategies as part of the post-approval change-management risk-mitigation strategy, which may enable a reduced stability data commitment and/or a reduced reporting category for change implementation.

Impact of Physicochemical Properties of Cellulosic Polymers on Supersaturation Maintenance in Aqueous Drug Solutions.

The precipitation inhibitory effect of cellulosic polymers in relation to their physicochemical properties was studied. Using a poorly water-soluble model drug, griseofulvin, the precipitation inhibitory effect of a series of hydroxypropyl methylcellulose (HPMC) and methylcellulose polymers was studied using solvent-shift method. The extent of supersaturation maintenance of each polymer was then quantified by the parameter, supersaturation factor (SF). Partial least square (PLS) regression analysis was employed to understand the relative contribution from viscosity, hydroxypropyl content (HC), methoxyl content, methoxyl/hydroxypropyl ratio, and drug-polymer interaction parameter (χ) on SF. All grades of cellulosic polymers effectively prolonged supersaturation of griseofulvin. PLS regression analysis revealed that HC and χ appeared to have the strongest influence on SF response. A regression model of SF = 1.65-0.16 χ + 0.05 HC with a high correlation coefficient, r of 0.921, was obtained. Since the value of χ is inversely related to the strength of drug-polymer interaction, the result shows that SF increases with increasing drug-polymer interaction and increasing HC. As such, it can be implied that strong drug-polymer interaction and presence of hydroxypropyl groups in cellulosic polymers for hydrogen bonding are two key parameters for effective supersaturation maintenance. This knowledge on the relative contribution of polymer physicochemical properties on precipitation inhibition will allow the selection of suitable cellulosic polymers for systematic development of supersaturating drug delivery systems.

Factor VII activating protease (FSAP) influences vascular remodeling in the mouse hind limb ischemia model.

BACKGROUND: Investigations in factor VII activating protease (FSAP)-/- mice suggest a role for FSAP in stroke, thrombosis and neointima formation. Here, we analyzed the role of FSAP in vascular remodeling processes related to arteriogenesis and angiogenesis in the mouse hind limb ischemia model. METHODS AND RESULTS: Femoral artery ligation was performed in mice and exogenous FSAP was injected locally to examine its effect on arteriogenesis in the adductor and angiogenesis in the gastrocnemius muscle over 21 days. Perfusion was decreased by FSAP, which was reflected in a lower arterial diameter and was associated with reduced monocyte infiltration in the adductor muscle. There was increased angiogenesis in the gastrocnemius muscle triggered indirectly by less blood supply to the lower limb. Comparison of wild-type (WT) and FSAP-/- mice showed that perfusion was not different between the genotypes but there were 2.5-fold more collateral arteries in the adductor muscle of FSAP-/- mice at day 21. This was associated with a higher infiltration of monocytes at day 3. Capillary density in the gastrocnemius muscle was not altered. Activity of the two major proteolytic pathways associated with vascular remodeling; matrix metalloprotease (MMP)-9 and urokinase-type plasminogen activator (uPA) was elevated in the gastrocnemius but not in the adductor muscle in FSAP-/- mice. CONCLUSIONS: Arteriogenesis is enhanced, and this is associated with a higher infiltration of monocytes, in the absence of endogenous FSAP but angiogenesis is unchanged. Exogenous FSAP had the opposite effect on arteriogenesis indicating a possible therapeutic potential of modulating endogenous FSAP.

High drug load, stable, manufacturable and bioavailable fenofibrate formulations in mesoporous silica: a comparison of spray drying versus solvent impregnation methods.

Encapsulation of drugs in mesoporous silica using co-spray drying process has been recently explored as potential industrial method. However, the impact of spray drying on manufacturability, physiochemical stability and bioavailability in relation to conventional drug load processes are yet to be fully investigated. Using a 2(3) factorial design, this study aims to investigate the effect of drug-loading process (co-spray drying and solvent impregnation), mesoporous silica pore size (SBA-15, 6.5 nm and MCM-41, 2.5 nm) and percentage drug load (30% w/w and 50% w/w) on material properties, crystallinity, physicochemical stability, release profiles and bioavailability of fenofibrate (FEN) loaded into mesoporous silica. From the scanning electronic microscopy (SEM) images, powder X-ray diffraction and Differential scanning calorimetry measurements, it is indicated that the co-spray drying process was able to load up to 50% (w/w) FEN in amorphous form onto the mesoporous silica as compared to the 30% (w/w) for solvent impregnation. The in vitro dissolution rate of the co-spray dried formulations was also significantly (p = 0.044) better than solvent impregnated formulations at the same drug loading. Six-month accelerated stability test at 40 °C/75 RH in open dish indicated excellent physical and chemical stability of formulations prepared by both methods. The amorphous state of FEN and the enhanced dissolution profiles were well preserved, and very low levels of degradation were detected after storage. The dog data for the three selected co-spray-dried formulations revealed multiple fold increment in FEN bioavailability compared to the reference crystalline FEN. These results validate the viability of co-spray-dried mesoporous silica formulations with high amorphous drug load as potential drug delivery systems for poorly water soluble drugs.