Key factors governing the reconstitution time of high concentration lyophilized protein formulations.

Lyophilized protein formulations containing highly concentrated proteins often have long and variable reconstitution times. Reconstitution time is dependent on a number of factors in a complex manner. Furthermore, factors influencing the reconstitution of partially crystalline cakes are reportedly different from those of amorphous cakes. The objectives of this work were to identify the key factors governing reconstitution and understand the mechanisms involved in reconstitution of both amorphous and partially crystalline cakes. Partial crystallinity in the final cake, larger pores and low "concentrated formulation viscosity" (i.e., viscosity near the surface of the dissolving cake) were identified as desirable characteristics for expediting reconstitution. Crystallinity and larger pores dramatically improved wettability and liquid penetration into partially crystalline cakes, ultimately resulting in well dispersed small pieces of partially dissolved cake. The smaller disintegrated cake pieces dissolved faster because of the increased surface area. The amorphous cakes exhibited poorer wettability than partially crystalline cakes. Moreover, the ability of the reconstitution fluid to penetrate the pores, and the resulting cake disintegration was much lower than that observed for partially crystalline cakes. In fact, for some of the amorphous cakes, the reconstitution fluid did not penetrate the cake at all. As a result, the undissolved intact cake or a large cake chunk floated on the reconstitution fluid amidst foam or bubbles generated during reconstitution. Dissolution of the floating cake appeared to proceed via gradual surface erosion where reconstitution time was found to be highly correlated with the viscosity near the surface of the dissolving cake solids. A higher viscosity prolonged reconstitution. Thus, both formulation and processing conditions can be tailored to achieve faster reconstitution. Including a crystallizable excipient proved to be beneficial. Incorporating an annealing step to facilitate crystallization of the crystallizable excipient and to promote larger pores was also found to be advantageous. A viscosity lowering excipient in the formulation could potentially be helpful but needs to be explored further.

Determination of Holdup Volume and Transient Contact Compatibility of Closed System Transfer Devices for a Reconstituted Lyophilized Drug Product.

Closed system transfer devices (CSTD) are broadly used in healthcare settings as an adjunct engineering control to limit personnel exposure to hazardous drugs (HD). Mechanistic and material differences between CSTD and traditional in-use devices warrant assessment of their impact to product quality and deliverable dose. A lyophilized antibody-drug conjugate (ADC) product was assessed for holdup volume and material compatibility with 14 diverse CSTD sets in a simulated dose compounding scheme. Transient exposure to CSTD showed no negative impact to product quality attributes; however, 6 CSTD sets showed a substantial increase in subvisible particles with a morphology consistent with silicone oil. CSTD led to variable but consistently reduced recovery of dose from the product. In addition, devices with high holdup volumes resulted in dilution of reconstituted drug product and protein concentrations below the target. Given the complexities and potential implications for efficacy and patient safety, this study illustrates the need for proactive assessment and risk mitigation, as well as increased awareness from clinicians, pharmaceutical manufacturers, device developers, and relevant regulatory authorities.

Consumers' Perceptions of the Australian Health Star Rating Labelling Scheme.

The objective of this study was to explore consumers' use and perception of the Australian Health Star Rating (HSR). A purposive sample of fifteen Australian grocery shoppers was recruited into four focus groups using a supermarket intercept strategy. Focus group discussions were recorded, transcribed and analysed using an iterative approach to thematic analysis. Three key themes emerged from analysis. The HSR was seen as simple, uncluttered, easy to understand and useful for quick comparison across products. The nutrition information was viewed positively; however, there was little confidence in the HSR due to a perceived lack of transparency in the criteria used to determine the number of stars. Highly processed foods were generally seen as having inflated ratings and participants expressed concern that this would increase consumption of these products. Finally, there was a belief that the HSR had a lack of negative imagery limiting the dissuasive impact on consumers when presented with low-rated foods. Consumers saw benefits in the HSR but were sceptical about how the ratings were derived. Transparency about the development and education on the application may assist with consumers' perception of the HSR.

Mechanisms by which crystalline mannitol improves the reconstitution time of high concentration lyophilized protein formulations.

Lyophilized high concentration protein formulations often have long and variable reconstitution times. The aim is to understand the role of crystalline mannitol in lowering the reconstitution time of these formulations. Novel methods were developed for quantifying the effect of crystalline mannitol on cake attributes influencing reconstitution, specifically, cake wettability, liquid penetration into the cake and cake disintegration. Amorphous and partially crystalline cakes were obtained by varying the freeze-drying conditions, particularly, the freezing rate (slow vs. fast), annealing (annealed vs. unannealed), and primary drying (aggressive vs. conservative). Mannitol crystallinity was quantified using X-ray powder diffractometry. Phase separation of crystalline mannitol from the amorphous, protein rich matrix improved wettability of the cake solids and promoted penetration of the reconstitution fluid into the cake interior. The partially crystalline cakes offered less resistance to crushing in the dry state than the amorphous cakes. Crystalline mannitol provided "weak points" in the freeze-dried cakes, potentially enabling easier cake disintegration upon addition of the reconstitution fluid. There was no evident correlation between the degree of crystallinity and reconstitution time. While crystalline mannitol generally decreased reconstitution time by favorably affecting the cake attributes influencing reconstitution, it did not always reduce reconstitution time.

Roller compaction, granulation and capsule product dissolution of drug formulations containing a lactose or mannitol filler, starch, and talc.

This study investigated the influence of excipient composition to the roller compaction and granulation characteristics of pharmaceutical formulations that were comprised of a spray-dried filler (lactose monohydrate or mannitol), pregelatinized starch, talc, magnesium stearate (1% w/w) and a ductile active pharmaceutical ingredient (25% w/w) using a mixed-level factorial design. The main and interaction effects of formulation variables (i.e., filler type, starch content, and talc content) to the response factors (i.e., solid fraction and tensile strength of ribbons, particle size, compressibility and flow of granules) were analyzed using multi-linear stepwise regression analysis. Experimental results indicated that roller compacted ribbons of both lactose and mannitol formulations had similar tensile strength. However, resulting lactose-based granules were finer than the mannitol-based granules because of the brittleness of lactose compared to mannitol. Due to the poor compressiblility of starch, increasing starch content in the formulation from 0% to 20% w/w led to reduction in ribbon solid fraction by 10%, ribbon tensile strength by 60%, and granule size by 30%. Granules containing lactose or more starch showed less cohesive flow than granules containing mannitol and less starch. Increasing talc content from 0% to 5% w/w had little effect to most physical properties of ribbons and granules while the flow of mannitol-based granules was found improved. Finally, it was observed that stored at 40 degrees C/75% RH over 12 weeks, gelatin capsules containing lactose-based granules had reduced dissolution rates due to pellicle formation inside capsule shells, while capsules containing mannitol-based granules remained immediate dissolution without noticeable pellicle formation.