Maria T. Cruanes

Meeting report: applied biopharmaceutics and quality by design for dissolution/release specification setting: product quality for patient benefit.

A biopharmaceutics and Quality by Design (QbD) conference was held on June 10–12, 2009 in Rockville, Maryland, USA to provide a forum and identify approaches for enhancing product quality for patient benefit. Presentations concerned the current biopharmaceutical toolbox (i.e., in vitro, in silico, pre-clinical, in vivo, and statistical approaches), as well as case studies, and reflections on new paradigms. Plenary and breakout session discussions evaluated the current state and envisioned a future state that more effectively integrates QbD and biopharmaceutics. Breakout groups discussed the following four topics: Integrating Biopharmaceutical Assessment into the QbD Paradigm, Predictive Statistical Tools, Predictive Mechanistic Tools, and Predictive Analytical Tools. Nine priority areas, further described in this report, were identified for advancing integration of biopharmaceutics and support a more fundamentally based, integrated approach to setting product dissolution/release acceptance criteria. Collaboration among a broad range of disciplines and fostering a knowledge sharing environment that places the patients needs as the focus of drug development, consistent with science- and risk-based spirit of QbD, were identified as key components of the path forward.

Quality-by-Design: Are We There Yet?

In 2012, the Quality-by-Design and Product Performance Focus Group of AAPS conducted a survey to assess the state of adoption and perception of Quality-by-Design (QbD). Responses from 149 anonymous individuals from industry—including consultants—(88%), academia (7%), and regulatory body (4%), were collected. A majority of respondents (54% to 76%) reported high frequency of utilization of several tools and most QbD elements outlined by International Conference on Harmonization Q8, with design of experiments, risk assessment, and the quality target product profile ranked as the top three. Over two thirds of respondents agreed that the benefits of QbD included both the positive impact it can have on the patient (78%), as well as on internal processes such as knowledge management (85%), decision making (79%), and lean manufacture (71%). However, more than 50% from industry were neutral about or disagreed with QbD leading to a better return on investment. This suggests that, despite the recognized scientific, manufacture, and patient-related benefits, there is not yet a clearly articulated business case for QbD available. There was a difference of opinion between industry and regulatory agency respondents as to whether a QbD-based submission resulted in increased efficiency of review. These contrasting views reinforce the idea that QbD implementation can benefit from further dialog between industry and regulatory authorities. A majority of respondents from academia indicated that QbD has influenced their research. In total, the results indicate the broad adoption of QbD but also suggest we are yet in a journey and that the process of gathering all experience and metrics required for connecting and demonstrating QbD benefits to all stakeholders is still in progress.

Effect of Added Alkalizer and Surfactant on Dissolution and Absorption of the Potassium Salt of a Weakly Basic Poorly Water-Soluble Drug

Telcagepant potassium salt (MK-0974) is an oral calcitonin gene-related peptide receptor inhibitor investigated for the treatment of acute migraine. Under gastric pH conditions, the salt rapidly gels, then converts to an insoluble neutral form that creates an impervious shell on the tablet surface, resulting in a slow and variable release dissolution rate and poor bioavailability. Early attempts to develop a solid dosage form, including solid dispersion and nanosuspension formulations, resulted in low exposures in preclinical studies. Thus, a liquid-filled soft gelatin capsule (SGC) formulation (oblong 20) was used for clinical studies. However, a solid dosage form was desirable for commercialization. The slow dissolution of the tablet formulations was overcome by using a basifying agent, arginine, and inclusion of a nonionic surfactant, poloxamer 407. The combination of arginine and poloxamer in the formulation created a local transient basic microenvironment that promoted the dissolution of the salt and prevented rapid precipitation of the neutral form on the tablet surface to form the gel layer. The tablet formulation achieved fast absorption and comparable exposure to the SGC formulation. The final optimized 280 mg tablet formulation was successfully demonstrated to be bioequivalent to the 300 mg SGC formulation.

Technical Note: Non-Sink Dissolution Media for Identification of Functional Formulation Excipients—The Case of a Precipitation Inhibitor

INTRODUCTION Due to the abundance of dissolution methodology and media available to pharmaceutical development and quality scientists, it is advisable that method selection criteria be dictated by the purpose of the measurement. This is particularly important when dissolution is used as a tool to guide formulation design. These cases often require the use of conditions that are relevant to the in vivo situation, but most critically, they are chosen to tease out an excipient’s ability to perform its intended function. This note aims to illustrate how purposeful media selection can help probe the functionality of an excipient to be used in a solid oral dosage form of a low solubility compound. In this example, the active pharmaceutical ingredient (API) is a crystalline potassium salt of a weak acid with a pKa = 6.8, and the excipient in question is hydroxypropyl methylcellulose (HPMC). The API has relatively high solubility, 71 mg/ mL in water or at a pH > pKa, which drops to 0.01 mg/ mL (the equilibrium solubility of the protonated free form measured more than 24 h after the crystalline salt was introduced in aqueous medium) at pH < 6.8, the pH expected in the gastrointestinal (GI) tract (1). The HPMC excipient was chosen for its potential ability to act as an antinucleating agent (2), inhibit precipitation of the drug at a pH < pKa, and induce super saturation, thus enhancing in vivo solubility and absorption. To assess the utility of the excipient for an oral dosage form, in vitro dissolution of the neat API is carried out under non-sink conditions, at a pH < pKa and a dose-relevant concentration, in the presence and absence of HPMC. Next, dissolution of the formulated API is carried out under non-sink conditions, over a pH range that is GI relevant, at dose-relevant concentrations. Subsequently, preclinical models are used to assess further the in vivo utility of the HPMC excipient before defining a formulation for human trials. A range of drug and excipient concentrations may be explored in vitro depending on predicted clinical doses and dosage form considerations, respectively. Two examples of in vitro measurements of neat and formulated API are presented below.