Strategies for Accelerated Drug Development: An Industry Perspective Based on an IQ Consortium Survey of CMC Considerations.

Over the past decade, there has been an increase in accelerated drug development with successful regulatory approval that has provided rapid access of novel medicines to patients world-wide. This has created the opportunity for the pharmaceutical industry to continuously improve the process of quickly bringing new medicines to patients with unmet medical needs. This can be accomplished through sharing the learnings and advancements in drug development, enhancing regulatory interactions, and collaborating with academics on developing the underlying science to reduce drug development timelines. In this paper, the IQ Consortium - Accelerated Drug Development working group members intend to share recommendations for optimizing strategies that build efficiencies in accelerated pathways for regulatory approval. Information was obtained by surveying member pharmaceutical companies with respect to recent expedited submissions within the past 5 years to gain insights as to which development strategies were successful. The learnings from this analysis are provided, which includes shared learnings in formulation development, stability, analytical methods, manufacturing, and importation testing as well as regulatory considerations. Each of these sections provide a summary illustrating the key data collected as well as a discussion that is aimed to guide pharmaceutical companies on strategies to consider streamlining development activities and expedite the drug to market.

Understanding Deformation Behavior and Compression Speed Effect in Gabapentin Compacts.

Deformation mechanism and strain rate sensitivity of gabapentin powder was investigated in this work. Heckel analysis, specific surface area and indentation hardness measurements revealed an intermediate yield pressure and brittle fracture as the dominant type of deformation mechanism during consolidation. Strain rate sensitivity of gabapentin was studied by compressing it at 1 mm/min and 500 mm/min compression speeds. Gabapentin demonstrated an atypical strain rate sensitivity in compactibility profile (tensile strength vs. solid fraction). Compacts of gabapentin compressed at fast speed showed an increase in tensile strength when compared with those compressed at slow speed. To understand the effect of compression speed on gabapentin's compactibility, PXRD analysis, surface area analysis, indentation hardness measurements, and consolidation modeling were performed. PXRD analysis carried out on compacts revealed no effect of speed on the physical solid-state stability of gabapentin. Specific surface area of compacts made at fast speed was higher than that of compacts made at slow speed. Indentation measurements performed on gabapentin compacts showed higher values of hardness in the case compacts made at fast speed. It was identified that at the fast compression speed, gabapentin shows greater particle fragmentation and form compacts with smaller pores.

Co-Processed Particles: An Approach to Transform Poor Tableting Properties.

The role of co-processing in improving tablet mechanical properties was investigated in this work. Gabapentin was used as the model compound owing to its poor tableting properties such as low tensile strength, strain rate sensitivity, high ejection force, and tablet capping. Gabapentin was blended with hydroxypropyl methylcellulose (Methocel®) in a high shear mixer to obtain an interactive mixture consisting of finer hydroxypropyl methylcellulose particles adsorbed onto the surface of larger gabapentin particles. Interactive mixture containing <1% by weight Methocel® was compressed on a material testing system (Instron®) to evaluate tablet mechanical properties. This co-processed gabapentin demonstrated improvement in tablet tensile strength and strain rate sensitivity which was attributed to improved particle bonding. In comparison, Methocel® 10% (w/w) low-shear mixture demonstrated strain rate sensitivity and lower tensile strength. Furthermore, Methocel® coating on gabapentin particles provided lubricity and decreased die-wall friction resulting in reduced tablet capping. This methodology has applications in improving mechanical properties of poorly compressible high-dose drugs without the use of high level of excipients. Furthermore, reduction in die-wall friction through particle surface coating could prove beneficial for formulations prone to overlubrication and slow dissolution owing to magnesium stearate.

Determination of Spatially Resolved Tablet Density and Hardness Using Near-Infrared Chemical Imaging (NIR-CI).

Near-infrared chemical imaging (NIR-CI) combines spectroscopy with digital imaging, enabling spatially resolved analysis and characterization of pharmaceutical samples. Hardness and relative density are critical quality attributes (CQA) that affect tablet performance. Intra-sample density or hardness variability can reveal deficiencies in formulation design or the tableting process. This study was designed to develop NIR-CI methods to predict spatially resolved tablet density and hardness. The method was implemented using a two-step procedure. First, NIR-CI was used to develop a relative density/solid fraction (SF) prediction method for pure microcrystalline cellulose (MCC) compacts only. A partial least squares (PLS) model for predicting SF was generated by regressing the spectra of certain representative pixels selected from each image against the compact SF. Pixel selection was accomplished with a threshold based on the Euclidean distance from the median tablet spectrum. Second, micro-indentation was performed on the calibration compacts to obtain hardness values. A univariate model was developed by relating the empirical hardness values to the NIR-CI predicted SF at the micro-indented pixel locations: this model generated spatially resolved hardness predictions for the entire tablet surface.

Physical characterization of drug:polymer dispersion behavior in polyethylene glycol 4000 solid dispersions using a suite of complementary analytical techniques.

Fifteen model drugs were quenched from 3:1 (w/w) mixtures with polyethylene glycol 4000 (PEG4000). The resulting solids were characterized using powder X-ray diffraction (PXRD), analysis of pair distribution function-transformed PXRD data (where appropriate), hot-stage polarized light microscopy, and differential scanning calorimetry (DSC). Drug/polymer dispersion behavior was classified using the data from each technique, independent of the others, and limitations to single-method characterization of PEG-based systems are highlighted. The data from all characterization techniques were collectively used to classify dispersion behavior, which was compared with single-technique characterization. Of the 15 combinations, only six resulted in solids whose dispersion behavior was consistently described using each standalone technique. The other nine were misclassified using at least one standalone technique, mainly because the phase behavior was ambiguously interpreted when only the data from one technique were considered. The data indicated that a suite of complementary techniques provided better classifications of the phase behavior. Of all the quenched solids, only cimetidine was fully dispersed in PEG4000, suggesting that it solidified from a completely miscible mixture of molten drug and polymer that did not phase separate upon cooling. In contrast, ibuprofen and PEG4000 completely recrystallized during preparation, whereas the remaining 13 drugs were partially dispersed in PEG4000 at this composition.

A material-sparing method for assessment of powder deformation characteristics using data collected during a single compression-decompression cycle.

Compressibility profiles, or functions of solid fraction versus applied pressure, are used to provide insight into the fundamental mechanical behavior of powders during compaction. These functions, collected during compression (in-die) or post ejection (out-of-die), indicate the amount of pressure that a given powder formulation requires to be compressed to a given density or thickness. To take advantage of the benefits offered by both methods, the data collected in-die during a single compression-decompression cycle will be used to generate the equivalent of a complete out-of-die compressibility profile that has been corrected for both elastic and viscoelastic recovery of the powder. This method has been found to be both a precise and accurate means of evaluating out-of-die compressibility for four common tableting excipients. Using this method, a comprehensive characterization of powder compaction behavior, specifically in relation to plastic/brittle, elastic and viscoelastic deformation, can be obtained. Not only is the method computationally simple, but it is also material-sparing. The ability to characterize powder compressibility using this approach can improve productivity and streamline tablet development studies.

Understanding deformation mechanisms during powder compaction using principal component analysis of compression data.

Principal component analysis (PCA) was applied to pharmaceutical powder compaction. A solid fraction parameter (SF(c/d)) and a mechanical work parameter (W(c/d)) representing irreversible compression behavior were determined as functions of applied load. Multivariate analysis of the compression data was carried out using PCA. The first principal component (PC1) showed loadings for the solid fraction and work values that agreed with changes in the relative significance of plastic deformation to consolidation at different pressures. The PC1 scores showed the same rank order as the relative plasticity ranking derived from the literature for common pharmaceutical materials. The utility of PC1 in understanding deformation was extended to binary mixtures using a subset of the original materials. Combinations of brittle and plastic materials were characterized using the PCA method. The relationships between PC1 scores and the weight fractions of the mixtures were typically linear showing ideal mixing in their deformation behaviors. The mixture consisting of two plastic materials was the only combination to show a consistent positive deviation from ideality. The application of PCA to solid fraction and mechanical work data appears to be an effective means of predicting deformation behavior during compaction of simple powder mixtures.