Current Approaches to Design Space Development and Regulatory Applications for Drug Products: Findings from the IQ Utilization of Design Space for Filings Working Group Survey.

PURPOSE: The concept of a Design Space (DSp) was introduced in ICH Q8 as a tool within the quality-by-design (QbD) approach to pharmaceutical development with the intent of being globally applicable. However, there appears to be variance in the regulatory agency expectations in pharmaceutical product filing and implementation of DSp. This paper presents some of the current industry perspective on design space. METHODS: The Utilization of Design Space for Filings (UDSpF) Working Group in the Innovation and Quality (IQ) Consortium conducted a survey to establish a baseline for the current understanding of DSp among IQ member companies and assess the similarities and/or differences in strategies when filing a DSp. The survey focused on how IQ member companies approach DSp development, the primary drivers for the DSp, the presentation of the DSp in the filing, DSp verification and the benefits and flexibility anticipated and/or realized. RESULTS: A total of 14 responses were received and analyzed representing a small sample size but a large proportion of the innovator industry/large pharmaceutical companies. The survey results revealed that DSp is not yet a commonplace for small molecule drug products and may not even be utilized as much in large molecule drug products. The benefits of DSp, with respect to enhanced process understanding, are well understood by the sponsors; however, the benefits of filed DSp with respect to manufacturing flexibility are not fully realized in the commercial lifecycle of the product. There are also challenges in gaining consistent buy-in/value proposition for DSp among cross-functional teams within organizations. CONCLUSIONS: There are still gaps in design space implementation for its full benefit in the pharmaceutical industry. The WG has presented a unified view from member companies on the approach to DSp considering when/where the DSp experiments are conducted and on the extent of the DSp development proposed in a dossier.

An assessment of powder pycnometry as a means of determining granule porosity.

A powder pycnometry method, using a commercially available instrument (GeoPyc® with DryFlo® displacement media), was evaluated as a means of measuring the envelope density of hydroxyapatite (HA) granules in the size range of 75-8000 µm. The aims of this study were to (1) investigate the reproducibility of the DryFlo® powder particle size and consolidation properties, (2) determine the number of preparation cycles required before test measurements should be taken, (3) compare the powder pycnometry method to the reference mercury porosimetry method and (4) investigate the effect of granule size on envelope density measurement. DryFlo® was shown to have a reproducible particle size when sampled at multiple locations across three separate containers. A minimum of 1 preparation cycle should be used to ensure consistent packing of the DryFlo® and HA granules. DryFlo® density was found to be insensitive to consolidation forces in the range of 10-100 N. The powder pycnometry method could be linearly calibrated against the reference mercury porosimetry method when considering polydisperse HA granule samples. However, when analyzing narrow particle size fractions limitations in the powder pycnometry method were noted resulting in a reduced particle size range of 1850-4050 µm that could be linearly calibrated against the mercury porosimetry method.

Accretion of the Earth and segregation of its core.

The Earth took 30-40 million years to accrete from smaller 'planetesimals'. Many of these planetesimals had metallic iron cores and during growth of the Earth this metal re-equilibrated with the Earth's silicate mantle, extracting siderophile ('iron-loving') elements into the Earth's iron-rich core. The current composition of the mantle indicates that much of the re-equilibration took place in a deep (> 400 km) molten silicate layer, or 'magma ocean', and that conditions became more oxidizing with time as the Earth grew. The high-pressure nature of the core-forming process led to the Earth's core being richer in low-atomic-number elements, notably silicon and possibly oxygen, than the cores of the smaller planetesimal building blocks.

The development of a growth regime map for a novel reverse-phase wet granulation process.

The feasibility of a novel reverse-phase wet granulation process has been established and potential advantages identified. Granule growth in the reverse-phase process proceeds via a steady state growth mechanism controlled by capillary forces, whereas granule growth in the conventional process proceeds via an induction growth regime controlled by viscous forces. The resultant reverse-phase granules generally have greater mass mean diameter and lower intragranular porosity when compared to conventional granules prepared under the same liquid saturation and impeller speed conditions indicating the two processes may be operating under different growth regimes. Given the observed differences in growth mechanism and consolidation behaviour of the reverse-phase and conventional granules the applicability of the current conventional granulation regime map is unclear. The aim of the present study was therefore to construct and evaluate a growth regime map, which depicts the regime as a function of liquid saturation and Stokes deformation number, for the reverse-phase granulation process. Stokes deformation number was shown to be a good predictor of both granule mass mean diameter and intragranular porosity over a wide range of process conditions. The data presented support the hypothesis that reverse-phase granules have a greater amount of surface liquid present which can dissipate collision energy and resist granule rebound resulting in the greater granule growth observed. As a result the reverse-phase granulation process results in a greater degree of granule consolidation than that produced using the conventional granulation process. Stokes deformation number was capable of differentiating these differences in the granulation process.

Late accretion on the earliest planetesimals revealed by the highly siderophile elements.

Late accretion of primitive chondritic material to Earth, the Moon, and Mars, after core formation had ceased, can account for the absolute and relative abundances of highly siderophile elements (HSEs) in their silicate mantles. Here we show that smaller planetesimals also possess elevated HSE abundances in chondritic proportions. This demonstrates that late addition of chondritic material was a common feature of all differentiated planets and planetesimals, irrespective of when they accreted; occurring ≤5 to ≥150 million years after the formation of the solar system. Parent-body size played a role in producing variations in absolute HSE abundances among these bodies; however, the oxidation state of the body exerted the major control by influencing the extent to which late-accreted material was mixed into the silicate mantle rather than removed to the core.