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.

Mechanistic Insights into Propylparaben Sorption on Polyvinyl Chloride.

The mechanism of loss of propylparaben potency from formulations when in contact with polyvinyl chloride has been determined. It is caused by the adsorption of propylparaben onto polyvinyl chloride surfaces. The adsorption kinetics is best described using a pseudo-second order model based on non-linear fit. The rate of adsorption increases with increasing bulk concentration of propylparaben. Adsorption equilibrium isotherm was fitted to three isotherm models: Langmuir, Freundlich, and Temkin, using non-linear fit. The Freundlich and Temkin models show the best fit, indicating a multi-layer adsorption. Using this case study, we present a methodology to provide mechanistic insights into the compatibility data between pharmaceutical ingredients and product contact materials when sorption is involved.

Prediction of Air Entrapment in Tableting: An Approximate Solution.

An approximate solution is presented for the prediction of air entrapment during tableting. Assuming weak coupling of the deformation of the solid phase, the flow of interstitial air and a set of reasonable additional geometric assumptions, the general problem is reduced to 1 dimension. Experimental values of air permeability through tablet specimens of commonly used pharmaceutical excipients were obtained using a 3D printed test cell outfitted to a powder rheometer. Using these values, combined with a numerical solution of the governing partial differential equation, parametric studies are presented that demonstrate the importance of permeability, compaction speed, tablet size, and punch-die tolerance on air entrapment. In addition, a first-order approximation of the role of entrapped air on the measured radial tensile strength of formed tablets is presented.

Maximizing the Impact of Physiologically Based Oral Absorption Modeling and Simulation.

The challenge of bringing innovative medicines to patients in combination with intense competition within the pharmaceutical industry has induced companies to develop quality medicines more efficiently and cost-effectively. State-of-the-art approaches to advance drug development have never been so urgent. One such approach that has been gaining traction within the industry is the application of modeling and simulation. In this commentary, the benefits of physiologically based oral absorption modeling and simulation in drug development are highlighted and suggestions for maximizing its impact are provided.

Utilizing physiologically based pharmacokinetic modeling to inform formulation and clinical development for a compound with pH-dependent solubility.

ARRY-403 is a glucokinase activator developed for the treatment of diabetes. Less than dose-proportional exposure was observed during single ascending dose studies with ARRY-403. A physiologically based pharmacokinetic (PBPK) model for ARRY-403 was developed through integration of in vitro physicochemical data with precipitation time estimations based on results from the single ascending dose studies; PBPK modeling indicated that the primary cause of the less than dose-proportional exposure was dose-limited absorption because of pH-dependent solubility. The impact of dose, particle size, and fasted or fed state on ARRY-403 exposure was examined through sensitivity analyses and used to refine the PBPK model. On the basis of the marked pH-dependent solubility of ARRY-403, the refined PBPK model was used to simulate the effects of acid-reducing agents (ARAs) on ARRY-403 exposure, as these agents are widely available and could be coadministered with ARRY-403. The simulations indicated that a clinical study with an ARA was warranted; in a clinical study, famotidine had a marked effect on ARRY-403 exposure. This approach, based on the "predict, learn, and confirm" paradigm, demonstrates the utility of integrating physicochemical properties, in vitro experiments, and clinical results using PBPK to inform formulation development and to guide clinical study design.

Evaluating and modifying Johanson's rolling model to improve its predictability.

The purpose of this study is to investigate if Johanson's rolling theory can correctly predict the maximum roll surface pressure during the roll compaction. Three model pharmaceutical formulations were roller compacted using the Gerteis Mini Pactor at multiple combinations of roll forces and roll gaps. The resultant ribbon density at each combination of roll force and roll gap was measured and the corresponding maximum roll surface pressure was predicted using Johanson's rolling model. The measured ribbon density and predicted maximum roll surface pressure from roller compactor was compared with the measured wafer density and maximum axial stress from die compression. The results indicate that predicted maximum roll surface pressure from roller compactor is higher than the axial stress from die compression to manufacture same density ribbons. The root cause of overprediction of maximum roll surface pressure from Johanson's model was found and corrected. The modified model offers reasonably accurate prediction of maximum roll surface pressure for all roller compaction experiments conducted in this study.

Isothermal microcalorimetry to investigate the phase separation for amorphous solid dispersions of AMG 517 with HPMC-AS.

Understanding the crystallization kinetics of an amorphous drug is critical for the development of an amorphous solid dispersion (ASD) formulation. This paper examines the phase separation and crystallization of the drug AMG 517 in ASDs of varying drug load at various conditions of temperature and relative humidity using isothermal microcalorimetry. ASDs of AMG 517 in hydroxypropyl methylcellulose acetate succinate (HPMC-AS) were manufactured using a Buchi 290 mini spray dryer system. ASDs were characterized using modulated differential scanning calorimetry (mDSC) and scanning electron microscopy (SEM) prior to isothermal microcalorimetry evaluation, and crystallinity was measured using (19)F solid state nuclear magnetic resonance spectroscopy (SSNMR), before and after crystallization. The crystallization of ASDs of AMG 517 in HPMC-AS was significantly slowed by the presence of HPMC-AS polymer, indicating enhanced physical stability for the ASD formulations. A two-phase crystallization was observed by isothermal microcalorimetry at temperatures near the glass transition temperature (Tg), indicating a drug-rich phase and a miscible ASD phase. (19)F SSNMR showed that only partial crystallization of the drug occurred for the ASDs, suggesting a third phase which did not crystallize, possibly representing a thermodynamically stable, soluble component. Isothermal microcalorimetry provides important kinetic data for monitoring crystallization of the drug in the ASDs and, together with (19)F SSNMR, suggests a three-phase ASD system for AMG 517 in HPMC-AS.

Enhancing and sustaining AMG 009 dissolution from a bilayer oral solid dosage form via microenvironmental pH modulation and supersaturation.

Enhancing and sustaining AMG 009 dissolution from a matrix tablet via microenvironmental pH modulation and supersaturation, where poorly soluble acidic AMG 009 molecule was intimately mixed and compressed together with a basic pH modifier (e.g., sodium carbonate) and nucleation inhibitor hydroxypropyl methylcellulose K100 LV (HPMC K100 LV), was demonstrated previously. However, not all acidic or basic drugs are compatible with basic or acidic pH modifiers either chemically or physically. The objective of this study is to investigate whether similar dissolution enhancement of AMG 009 can be achieved from a bilayer dosage form, where AMG 009 and sodium carbonate are placed in a separate layer with or without the addition of HPMC K100 LV in each layer. Study results indicate that HPMC K100 LV-containing bilayer dosage forms gained similar dissolution enhancement as matrix dosage forms did. Bilayer dosage forms without HPMC K100 LV benefitted the least from dissolution enhancement.

Enhancing and sustaining AMG 009 dissolution from a matrix tablet via microenvironmental pH modulation and supersaturation.

The objective of this study was to investigate the combined effect of pH modifiers and nucleation inhibitors on enhancing and sustaining the dissolution of AMG 009 tablet via supersaturation. Several bases and polymers were added as pH modifiers and nucleation inhibitors, respectively, to evaluate their impact on the dissolution of AMG 009 tablets. The results indicate that sodium carbonate, among the bases investigated, enhanced AMG 009 dissolution the most. HPMC E5 LV, among the nucleation inhibitors tested, was the most effective in sustaining AMG 009 supersaturation. The release of AMG 009 went from 4% for tablets which did not contain both sodium carbonate and HPMC E5 LV to 70% for the ones that did, resulting in a 17.5-fold increase in the extent of dissolution. The effect of compression force and disintegrant on the dissolution of tablets were also evaluated. The results indicate that compression force had no effect on AMG 009 release. The addition of disintegrating agents, on the other hand, decreased the dissolution of AMG 009.

Manufacture and performance evaluation of a stable amorphous complex of an acidic drug molecule and Neusilin.

In this paper, we explore the use of Neusilin, an inorganic magnesium aluminometasilicate, to stabilize the amorphous form of an acidic drug Sulindac. Both cryomilling and ball milling of the drug with Neusilin were found to produce the amorphous phase. However, the ball-milled (BM) material exhibited superior physical stability when compared with the cryomilled material at 40°C/75% relative humidity. (13) C solid-state nuclear magnetic resonance investigation of the BM material revealed an acid-base reaction between Sulindac and Neusilin. Optimal milling conditions and the kinetics of salt formation were also established. As benchtop milling is a laboratory-scale process, a scalable process was developed to make Sulindac-Neusilin amorphous drug complex using hot-melt extrusion (HME). The dissolution properties of the resulting HME material was found to have been improved over the material made by benchtop milling while maintaining similar physical stability. The HME material was used to make tablets using a direct compression method. The HME tablets were found to have better dissolution properties than tablets made from crystalline Sulindac. For the broad class of acidic drugs containing the carboxyl moiety, inorganic silicates such as Neusilin would offer a better choice than organic polymers to stabilize the amorphous phase.

The manufacture of low-dose oral solid dosage form to support early clinical studies using an automated micro-filing system.

Automated powder dispensing systems enable supplying early clinical studies using drug-in-capsule approach, which is material sparing and requires a minimum amount of resources. However, the inability of accurately filling the capsule with a small amount, e.g., several micrograms, of drug limits the use of these systems for potent drugs. We demonstrate that formulated powder blends can be used to successfully fill capsules containing 5 µg to 5 mg of drug with adequate content uniformity. Effective formulation and process strategies that enable this approach are presented with examples.

Application of twin screw extrusion in the manufacture of cocrystals, part I: four case studies.

The application of twin screw extrusion (TSE) as a scalable and green process for the manufacture of cocrystals was investigated. Four model cocrystal forming systems, Caffeine-Oxalic acid, Nicotinamide-trans cinnamic acid, Carbamazepine-Saccharin, and Theophylline-Citric acid, were selected for the study. The parameters of the extrusion process that influenced cocrystal formation were examined. TSE was found to be an effective method to make cocrystals for all four systems studied. It was demonstrated that temperature and extent of mixing in the extruder were the primary process parameters that influenced extent of conversion to the cocrystal in neat TSE experiments. In addition to neat extrusion, liquid-assisted TSE was also demonstrated for the first time as a viable process for making cocrystals. Notably, the use of catalytic amount of benign solvents led to a lowering of processing temperatures required to form the cocrystal in the extruder. TSE should be considered as an efficient, scalable, and environmentally friendly process for the manufacture of cocrystals with little to no solvent requirements.

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.