Colleen Ruegger

Optimization of formulation and process parameters for the production of nanosuspension by wet media milling technique: Effect of Vitamin E TPGS and nanocrystal particle size on oral absorption

The purpose of this study was to develop nanosuspension formulations of a poorly soluble drug using a wet media milling technique. The milling process was optimized by studying the effects of critical process parameters on the size of nanoparticles using a factorial design approach. During the design of experiments (DOEs) study, different concentrations of Vitamin E TPGS in the suspensions were used to evaluate its influence on the stabilization of a nanosuspension. Once the final formulation was optimized, a pharmacokinetic study was performed in beagle dogs to investigate the effect of different ranges of particle size of nanocrystals on the plasma profile. A significant increase in AUC and C(max) was observed when the drug substance was converted into nanocrystals, likely due to the increase in dissolution rate. Results also revealed that the nanosuspension formulation (consists of nanocrystals with narrow size distribution, having a mean particle size<300 nm) produced less variability with regards to the individual plasma concentrations in the dogs when compared an alternate nanocrystal formulation (consists of nanocrystals with broad size distribution having a mean particle size<750 nm). This type of observation can be explained due to the Ostwald ripening phenomena between the nanocrystals when the particle size distribution was very broad (higher poly dispersity index). Surprisingly, the un-micronized suspension containing Vitamin E TPGS did not show any significant impact on pharmacokinetic parameters.

Application of spray granulation for conversion of a nanosuspension into a dry powder form

The in vivo effect of particle agglomeration after drying of nanoparticles has not been extensively studied till date based on current literature review. The purpose of this research was to evaluate the feasibility of spray granulation as a processing method to convert a nanosuspension of a poorly water soluble drug into a solid dosage form and to evaluate the effect of the transformation into a solid powder on the in vivo exposure in beagle dogs. Formulation variables like the level of stabilizer in the nanosuspension formulation, granulation substrate and drug loading in the granulation were evaluated. The granules were characterized for moisture content, drug content, particle size, crystallinity and in vitro dissolution rate. Granulations with 10% drug loading showed dissolution profiles comparable to the nanosuspension, slightly slower dissolution profiles were observed at 20% drug loading. This can be attributed to an increase in the surface hydrophobicity at a higher drug loading and the formation of agglomerates that were harder to disintegrate, thereby compromising the dissolution rate. An in vivo PK study in beagle dogs showed an 8-fold increase and a 6-fold increase in the AUC(0-48) from the nanosuspension and dried nanosuspension formulations respectively compared to the coarse suspension. Also, the nanosuspension and dried nanosuspension formulations showed a 12-fold and 8-fold increase in the C(max) respectively compared to the coarse suspension. This shows the feasibility of using spray granulation as a processing method to convert a nanosuspension into a solid dosage form with improved in vivo exposure compared to the coarse suspension formulation.

The effect of compression and decompression speed on the mechanical strength of compacts

The purpose of this work was to investigate the effect of punch speed on the compaction properties of pharmaceutical powders; in particular, to separate out differences between the effect of the compression and decompression events. Tablets were prepared using an integrated compaction research system. Various “sawtooth” punch profiles were followed to compare the effects of different punch speeds on the crushing strength of the resulting tablets. The loading and unloading speeds were varied independently of one another. In general, when the compression speed was equal to the decompression speed, the tablet crushing strength was observed to decrease as the punch velocity increased. When the compression speed was greater than or less than the decompression speed, the results varied, depending on the material undergoing compaction. Reduction of the unloading speed from 300 to 10 mm/sec for pregelatinized starch and microcrystalline cellulose produced a significant increase in crushing strength, whereas no significant increase in crushing strength was observed until the loading speed was reduced to 10 mm/sec. Reduction of the unloading speed had a similar effect on the direct compression (DC) ibuprofen, however, even greater improvement in the crushing strength was observed when the loading speed was reduced. No improvement in the DC acetaminophen tablets was observed when the unloading speed was reduced, however, a significant increase in crushing strength was produced when the rate of loading was reduced. This work showed that the strength of tablets can be improved and some tableting problems such as capping can be minimized or prevented by modifying the rates of loading/unloading.

The influence of varying precompaction and main compaction profile parameters on the mechanical strength of compacts

The purpose of this work was to investigate how altering the method of force application could be beneficial to tablet production in order to increase tablet strength and eliminate or minimize the incidence of capping and lamination. An integrated compaction research system (i.e., compaction simulator) was used throughout this study. Compaction profiles containing a single compaction event and a double (pre- and main) compaction event were created. The ratio and magnitude of the pre- and main compaction pressures were varied and the time interval between the pre- and main compaction events was altered to determine the effects on the crushing strengths and capping tendency of the final compacts. In all cases, for a given pressure, the double compaction event produced stronger tablets than the single compaction event. When the ratio and magnitude of the pre- and main compaction pressures were varied, the results differed depending on the material undergoing compaction. Dicalcium phosphate/microcrystalline cellulose and pregelatinized starch tablets had no significant difference in crushing strength values regardless of whether the precompaction pressure was less than or greater than the main compaction pressure. However, both direct compression (DC) acetaminophen and DC ibuprofen were found to have increased crushing strengths and decreased capping/lamination when the precompaction pressure was less than the main compaction pressure. When the time interval between the pre- and main compaction events was varied from 30 to 500 msec, no significant difference in the crushing strength or capping/lamination tendency was observed. It was concluded that the effect of altering the ratio and magnitude of the pre- and main compaction pressures varied from one material to another, suggesting that the profiles should be tailored individually for the specific material undergoing compaction.

Best Practices for the Development, Scale-up, and Post-approval Change Control of IR and MR Dosage Forms in the Current Quality-by-Design Paradigm

In this whitepaper, the Manufacturing Technical Committee of the Product Quality Research Institute provides information on the common, best practices in use today in the development of high-quality chemistry, manufacturing and controls documentation. Important topics reviewed include International Conference on Harmonization, in vitro–in vivo correlation considerations, quality-by-design approaches, process analytical technologies and current scale-up, and process control and validation practices. It is the hope and intent that this whitepaper will engender expanded dialog on this important subject by the pharmaceutical industry and its regulatory bodies.

Examining Manufacturing Readiness for Breakthrough Drug Development.

In July 2012, Congress passed the Advancing Breakthrough Therapies for Patients Act as part of the Food and Drug Administration Safety and Innovation Act (FDASIA). Section 902 of FDASIA provides for designation of a drug as a breakthrough therapy Bif the drug is intended alone or in combination with one or more other drugs, to treat serious or life-threatening diseases or conditions and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies (1).^ Breakthrough designation is a mechanism that the U.S. Food and Drug Administration (FDA) can grant to sponsors to expedite the development of these promising therapies. As part of the program, the FDA and sponsor collaborate in a dynamic, multi-disciplinary, resource-intensive process to determine the most efficient path using an Ball hands on deck approach^ involving senior managers and experienced review staff and more frequent and interactive communications (2,3). The objective is to expedite design and review of the clinical development program so that trials are as efficient as possible, and the number of patients exposed to potentially less efficacious treatment is minimized. As a consequence, clinical development timelines involving the traditional three distinct phases could be reduced from 7–10 to 3–5 years. The shorter clinical development programs will have significant impact on product and process development timelines requiring the manufacturing organization to reconsider traditional approaches to product and process development and undertake their own resource-intensive, cross-functional team approach to ensure a sustained supply of safe and efficacious product at the time of approval. To ensure success, the manufacturing organization should have good communications with the clinical organization to facilitate identification of potential candidates for breakthrough designation early and help gate or accelerate the appropriate Chemistry, Manufacturing, and Controls (CMC) and current Good Manufacturing Practice (cGMP) development activities. It is important to understand that breakthrough drug development programs are resource intensive; sponsors need to be selective about which programs to take forward and ensure management support. Moreover, a collaborative, cross-functional approach between development, commercial, and regulatory operations, with early and robust discussions, is essential to ensure successful development and launch of a breakthrough drug product. In March of 2015, Friends of Cancer Research (Friends) convened a group of industry and FDA stakeholders familiar with developing breakthrough drugs to explore options, The opinions expressed in this manuscript are those of Earl Dye, Annie Sturgess, Gargi Maheshwari, Kimberly May, Colleen Ruegger, Usha Ramesh, Heow Tan, Keith Cockerill, John Groskoph, Emanuela Lacana, Sau Lee, and Sarah Pope Miksinski and do not necessarily reflect the views or policies of the FDA.